RU2572244C2 - Aromatase inhibitors - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula V or Va and their pharmaceutically acceptable salts. In formula V

or Va

D is selected from the group, including linear hydrocarbon groups, which contain carbon chain, containing from 1 to 2 carbon atoms; R₄ stands for -CN; R₂ and R₅ stand for H; each of R₃ and R₆ is independently selected from the group, including -H, halogen, -NR₁₂R₁₃ and -(CH₂)_0-1R₁₄; R₁₂ and R₁₃ together with atoms, which they are bound to, can form monocyclic ring, containing from 5 to 8 ring elements; R₁₄ stands for

each of R₁₇-R₂₁ is independently selected from the group, including -H, halogen, -O-(C₁-C₆)halogenalkyl, -CN, -OH, -OBn, -OSO₂NR₁₅R₁₆, -O-(C₁-C₆)alkyl; R₁₅ and R₁₆ are selected from H; each of R₇-R₁₁ is independently selected from the group, including -H, halogen, -OH, -OBn, -OSO₂NR₁₅R₁₆; R₁₅ and R₁₆ are independently selected from the group, including H Invention also relates to pharmaceutical composition.

EFFECT: invention compounds possess inhibiting activity with respect to STS and/or aromatase.

25 cl, 2 dwg

Description

FIELD OF THE INVENTION

The present invention relates to a compound.

In particular, the present invention relates to a compound and to a pharmaceutical composition comprising this compound. The present invention also relates to the use of a compound or composition containing this compound in therapy.

BACKGROUND

Available data show that estrogens are the main mitogens involved in the growth of tumors in endocrine-dependent tissues, such as the mammary gland and the endometrium. Although plasma estrogen concentrations are similar in women with and without breast cancer, the levels of estrone and estradiol in a breast tumor are higher than in normal breast or blood tissue. It is believed that in situ synthesis of estrogen makes a significant contribution to the high concentration of estrogen in tumors, and therefore inhibitors, especially specific inhibitors of estrogen biosynthesis, are potentially relevant for the treatment of endocrine-dependent tumors.

Over the past two decades, considerable interest has been shown in the development of aromatase pathway inhibitors — which converts the androgen precursor, androstenedione, to estrone. However, there is currently evidence that the estronsulfatase pathway (E1-STS), i.e. hydrolysis of estronsulfate to form estrone (conversion of E1S to E1) and aromatase (i.e., the conversion of androstenedione to estrone) provides the formation of estrogens in breast tumors.

1 and 2 are diagrams showing some of the enzymes involved in the in situ synthesis of estrone from estronsulfate, estradiol, and androstenedione.

2, which schematically shows the origin of estrogenic steroids in postmenopausal women, “ER” refers to the estrogen receptor, “DHA-S” refers to dehydroepiandrosterone sulfate, “Adiol” refers to androstenediol, “E1-STS” refers to estronsulfatase, “DHA-STS "stands for DHA sulfatase," Adiol-STS "stands for androstenediol sulfatase, and" 17B-HSD "stands for estradiol-17B-hydroxysteroid dehydrogenase.

It can be seen that the two main enzymes that are involved in peripheral estrogen synthesis are the aromatase enzyme and the estronsulfatase enzyme.

In a brief description, the aromatase enzyme converts androstenedione, which is produced in large quantities by the adrenal cortex, into estrone. Recent evidence suggests that some flavones can inhibit aromatase activity.

However, a significant part of the estrone formed in this way is converted to estronsulfate (E1S) and there is a lot of data currently showing that in plasma and tissues E1S acts as a reservoir for the formation of estrone when exposed to estronsulfatase.

In this regard, it is currently believed that the estronsulfatase pathway (E1-STS) is i.e. hydrolysis of estronsulfate to form estrone (conversion of E1S to E1) is one of the main sources of estrogen in breast tumors. This theory is supported by a slight decrease in estrogen concentrations in postmenopausal women with breast cancer who were treated with aromatase inhibitors such as aminoglutethimide and 4-hydroxyandrostenedione, and the fact that these patients who were treated with an aromatase inhibitor had a plasma concentration of E1S remains relatively high. This theory is also supported by the long half-life of E1S from the blood (10-12 h) compared with unconjugated estrogens (20 min) and the high activity of steroid sulfatase in the liver and normal and malignant mammary tissues.

Thus, the formation of estrogen in the malignant tissues of the breast and endometrium along the sulfatase pathway makes a significant contribution to the high concentration of estrogen in these tumors. However, inhibition of aromatase and sulfatase pathways can provide significant therapeutic benefits.

PCT / GB92 / 01587 discloses novel steroid sulfatase inhibitors and pharmaceutical compositions containing them for use in the treatment of estrone-dependent tumors, in particular breast cancer. These steroid steroid sulfatase inhibitors are sulfamates, such as N, N-dimethylestron-3-sulfamate and, preferably, estrone-3-sulfamate (also known as EMATE). EMATE has the following structure:

EMATE is known to be an active inhibitor of E1-STS, since at 0.1 nM it provides a greater than 99% inhibition of E1-STS in intact MCF-7 cells. EMATE also inhibits the E1-STS enzyme in a time and concentration dependent manner, which indicates that it acts as an active site-specific inactivator. Although EMATE was originally designed to inhibit E1-STS, it also inhibits dehydroepiandrosterone sulfonase (DHA-STS), which is an enzyme that is thought to play a major role in the regulation of the biosynthesis of the estrogen steroid androstenediol. In addition, there is now evidence that androstenediol may be even more important as a stimulator of breast tumor growth. EMATE is also active in vivo, almost completely inhibiting the activity of E1-STS (99%) and DHA-STS (99%) in rat liver, which occurs when it is administered orally or subcutaneously. In addition, it has been shown that EMATE improves memory in rats. Studies in mice indicate a relationship between DHA-STS activity and regulation of part of the immune response. It is believed that this can also occur in people. The bridging atom O of the sulfate moiety of EMATE is important for inhibitory activity. So, if the 3-O atom is replaced by other heteroatoms, as in estrone-3-N-sulfamate and estron-3-S-sulfamate, these analogs are weaker and time-independent inactivators.

In addition to estrone, another important steroid with estrogenic characteristics that is produced in postmenopausal women is androstenediol (see FIG. 2).

Androstenediol, although it is an androgen, can bind to an estrogen receptor (ER) and can stimulate ER-positive breast cancer cells and the growth of carcinogen-induced breast tumors in rats. It is important that in postmenopausal women 90% of the produced androstenediol is formed from androgen dehydroepiandrosterone sulfate (DHA-S), which is produced in large quantities by the adrenal cortex. DHA-S is converted to DHA by DHA-sulfatase, which may be the same enzyme as estronsulfatase, which provides hydrolysis of E1S, or be different from it.

Over the past 10-15 years, a significant amount of research has been conducted on the development of active aromatase inhibitors, and some of them are commercially available. However, according to three recent research reports on post-menopausal women with breast cancer treated with aromatase inhibitors, E1S concentrations remained in the range of 400-1000 pg / ml.

Therefore, in summary, we can say that in situ estrogen synthesis apparently contributes to the high estrogen content in tumors, and therefore specific inhibitors of estrogen synthesis can be useful for the treatment of endocrine-dependent tumors.

In addition, although the formation of estrogen in the malignant tissues of the breast and endometrium along the sulfatase pathway makes a large contribution to high concentrations of estrogens, there are other enzymatic pathways that contribute to in vivo estrogen synthesis.

The present invention relates to the development and preparation of new compounds useful for inhibiting steroid sulfatase activity and aromatase activity.

BRIEF DESCRIPTION OF THE OBJECTS OF THE PRESENT INVENTION

The present invention is based on the unexpected finding that certain polycyclic compounds can be used as effective steroid sulfatase inhibitors and / or aromatase inhibitors and / or agents that can affect the cell cycle and / or agents that can affect apoptosis.

In one aspect, the present invention is based on the unexpected finding that certain polycyclic compounds can be used as effective steroid sulfatase inhibitors and / or aromatase inhibitors and / or as cell cycle modulators and / or as apoptosis modulators.

Polycyclic compounds contain at least a central trivalent or tetravalent atom to which at least three ring systems are attached directly or indirectly via a bridge. At least one of the ring systems contains —CN as a substituent of the ring system. The compounds of the present invention may contain other substituents. These other substituents may, for example, further increase the activity of the compounds of the invention and / or increase stability (ex vivo and / or in vivo).

DETAILED DESCRIPTION OF THE OBJECTS OF THE PRESENT INVENTION

One object of the present invention is a compound of formula I

in which Z is selected from the group consisting of N and CR ₂₂ , where R ₂₂ is H or a bond with D;

in which D is selected from the group comprising a bond, C = O and linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, where the carbon chain optionally contains an oxy group (= O), ether (-O-) or a simple thioether (-S-) bridge,

in which R _{1 is} selected from the group consisting of: triazolyl, imidazolyl, pyrimidinyl radical,

where each of R ₂ —R _{6 is} independently selected from the group consisting of —H, —CN, NO ₂ , halogen,

-N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ] and - (CH ₂ ) _0-1 R ₁₄ ,

or two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring,

where at least one of R ₂ —R ₆ is —CN,

where (i) at least one of R ₂ -R ₆ is - (CH ₂ ) _0-1 R ₁₄ , or

(ii) at least one of R ₂ —R ₆ is —N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ], or

(iii) at least two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring, or

(iv) at least one of R ₂ —R ₆ is - (CH ₂ ) _0-1 —O-R ′ ₁₄ ,

where R ₁₂ and R _{13 are} independently selected from the group consisting of H, linear or branched hydrocarbon groups having a carbon chain containing from 1 to 10 carbon atoms,

or together with the atoms to which they are attached, can form a mono- or bicyclic ring containing from 5 to 14 ring elements, where R _{14 is} selected from the group consisting of:

- aliphatic ring systems;

- unsubstituted or substituted monocyclic aliphatic heterocycles;

- unsubstituted or substituted heteroaryl radical and

- unsubstituted or substituted phenyl group;

- group of the formula

где t равно 1 или 2

where t is 1 or 2

wherein R _'14 represents an unsubstituted or substituted phenyl group; where each of R ₇ -R _{11 is} independently selected from the group consisting of -H, NO ₂ , halogen, -O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OPh, —OBn, —Ph, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —O- (C ₁ -C ₆ ) alkyl , - (C = O) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more sludge heteroatoms groups;

or any pharmaceutically acceptable salt thereof,

and preferably a compound of formula I,

in which Z is selected from the group consisting of N and CR ₂₂ , where R ₂₂ is H or a bond with D;

in which D is selected from the group consisting of a bond, C = O and linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, where the carbon chain optionally contains ether (-O-) or thioether (-S -) bridge, wherein R ₁ is selected from the group consisting of triazolyl, imidazolyl, pyrimidinyl radical

where each of R ₂ -R _{6 is} independently selected from the group consisting of —H, NO ₂ , halogen, —CN,

-N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ] and - (CH ₂ ) _0-1 R ₁₄ ,

or two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring,

where at least one of R ₂ —R ₆ is —CN,

where (i) at least one of R ₂ -R ₆ is - (CH ₂ ) _0-1 R ₁₄ , or

(ii) at least one of R ₂ —R ₆ is —N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ],

or

(iii) at least two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring, or

where R ₁₂ and R _{13 are} independently selected from the group consisting of H, linear or branched hydrocarbon groups having a carbon chain containing from 1 to 10 carbon atoms,

or together with the atoms to which they are attached, can form a mono- or bicyclic ring containing from 5 to 14 ring elements,

where R ₁₄ selected from the group including:

- aliphatic ring systems;

- unsubstituted or substituted monocyclic aliphatic heterocycles;

- unsubstituted or substituted heteroaryl radical and

- unsubstituted or substituted phenyl group;

where each of R ₇ -R _{11 is} independently selected from the group consisting of -H, NO ₂ , halogen, -O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OPh, —OBn, —Ph, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —O- (C ₁ -C ₆ ) alkyl , - (C = O) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups; or any pharmaceutically acceptable salt thereof.

In the context of the present invention, a pharmaceutically acceptable salt refers to an addition salt of said product of the present invention with pharmaceutically acceptable mineral or organic or inorganic acids. As salts with pharmaceutically acceptable inorganic acids, hydrochloride, hydrobromide, sulfate, phosphate, diphosphate and nitrate can be mentioned. As salts with pharmaceutically acceptable organic acids, acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate and stearate can be mentioned. Other examples of pharmaceutically acceptable salts are given in Salt selection for basic drugs, Int. J. Pharm. (1986), 33, 201-217.

One object of the present invention is a pharmaceutical composition comprising a compound of the present invention, optionally in admixture with a pharmaceutically acceptable carrier, diluent, excipient or excipient.

One object of the present invention is the use of a compound of the present invention for the manufacture of a medicament for use in the treatment of a pathological condition or disease associated with sulfatase (STS) and / or aromatase and / or cell cycle and / or apoptosis , and / or cell growth.

One object of the present invention is the use of a compound of the present invention for the manufacture of a medicament for use in the treatment of a pathological condition or disease associated with undesirable concentrations of STS and / or undesirable concentrations of aromatase and / or cell cycle, and / or apoptosis and / or cell growth.

One object of the present invention is the use of a compound of the present invention for the manufacture of a medicament for inhibiting STS activity and / or inhibiting aromatase activity.

One object of the present invention is the use of a compound of the present invention for the preparation of a medicament for inhibiting STS activity and inhibiting aromatase activity.

One object of the present invention is the use of a compound for the preparation of a medicament for use in the treatment of a pathological condition or disease associated with aromatase and optionally associated with STS, where the compound is described by formula I

in which Z is selected from the group consisting of N and CR ₂₂ , where R ₂₂ is H or a bond with D;

in which D is selected from the group consisting of a bond, C = O and linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, where the carbon chain optionally contains an oxy group (= O), ether (-O-) or a simple thioether (-S-) bridge,

wherein R ₁ is selected from the group consisting of triazolyl, imidazolyl, pyrimidinyl radical, where each of R ₂ -R ₆ are independently selected from the group consisting of -H, -CN, NO _2, halogen,

-N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ] and - (CH ₂ ) _0-1 R ₁₄ ,

or two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring,

where at least one of R ₂ —R ₆ is —CN,

where (i) at least one of R ₂ -R ₆ is - (CH ₂ ) _0-1 R ₁₄ , or

(ii) at least one of R ₂ —R ₆ is —N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ], or

(iii) at least two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring, or

(iv) at least one of R ₂ —R ₆ is - (CH ₂ ) _0-1 —O-R ′ ₁₄ ,

where R ₁₂ and R _{13 are} independently selected from the group consisting of H, linear or branched hydrocarbon groups having a carbon chain containing from 1 to 10 carbon atoms,

or together with the atoms to which they are attached, can form a mono- or bicyclic ring containing from 5 to 14 ring elements,

where R ₁₄ selected from the group including:

- aliphatic ring systems;

- unsubstituted or substituted monocyclic aliphatic heterocycles;

- unsubstituted or substituted heteroaryl radical and

- unsubstituted or substituted phenyl group;

- group of the formula

где t равно 1 или 2

where t is 1 or 2

wherein R _'14 represents an unsubstituted or substituted phenyl group;

where each of R ₇ -R _{11 is} independently selected from the group consisting of -H, NO ₂ , halogen, -O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OPh, —OBn, —Ph, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —O- (C ₁ -C ₆ ) alkyl , - (C = O) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups;

or any pharmaceutically acceptable salt thereof,

and preferably a compound of formula I,

in which Z is selected from the group consisting of N and CR ₂₂ , where R ₂₂ is H or a bond with D;

in which D is selected from the group consisting of a bond, C = O and linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, where the carbon chain optionally contains ether (-O-) or thioether (-S -) bridge,

in which R _{1 is} selected from the group consisting of: triazolyl, imidazolyl, pyrimidinyl radical,

where each of R ₂ -R _{6 is} independently selected from the group consisting of —H, NO ₂ , halogen, —CN,

-N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ] and - (CH ₂ ) _0-1 R ₁₄ ,

or two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring,

where at least one of R ₂ —R ₆ is —CN,

where (i) at least one of R ₂ -R ₆ is - (CH ₂ ) _0-1 R ₁₄ , or

(ii) at least one of R ₂ —R ₆ is —N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ], or

(iii) at least two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring, or

where R ₁₂ and R _{13 are} independently selected from the group consisting of H, linear or branched hydrocarbon groups having a carbon chain containing from 1 to 10 carbon atoms,

or together with the atoms to which they are attached, may form a mono- or bicyclic ring containing 5 to 14 ring members, where R ₁₄ is selected from the group consisting of:

- aliphatic ring systems;

- unsubstituted or substituted monocyclic aliphatic heterocycles;

- unsubstituted or substituted heteroaryl radical and

- unsubstituted or substituted phenyl group;

where each of R ₇ -R _{11 is} independently selected from the group consisting of -H, NO ₂ , halogen, -O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OPh, —OBn, —Ph, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —O- (C ₁ -C ₆ ) alkyl _{, - (C = O) 0-1} NR ₂₉ R ₃₀ or -CO (O) _0-1 R _31;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups; or any pharmaceutically acceptable salt thereof.

One object of the present invention is the use of a compound for the preparation of a medicament for use in the treatment of a pathological condition or disease associated with undesirable concentrations of aromatase and optionally associated with undesirable concentrations of STS, wherein the compound is described by formula I

in which Z is selected from the group consisting of N and CR ₂₂ , where R ₂₂ is H or a bond with D;

in which D is selected from the group consisting of a bond, C = O and linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, where the carbon chain optionally contains an oxy group (= O), ether (-O-) or a simple thioether (-S-) bridge,

in which R _{1 is} selected from the group consisting of: triazolyl, imidazolyl, pyrimidinyl radical,

where each of R ₂ —R _{6 is} independently selected from the group consisting of —H, —CN, NO ₂ , halogen,

-N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ] and - (CH ₂ ) _0-1 R ₁₄ ,

or two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring,

where at least one of R ₂ —R ₆ is —CN,

where (i) at least one of R ₂ -R ₆ is - (CH ₂ ) _0-1 R ₁₄ , or

(ii) at least one of R ₂ —R ₆ is —N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ], or

(iii) at least two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring, or

(iv) at least one of R ₂ —R ₆ is - (CH ₂ ) _0-1 —O-R ′ ₁₄ ,

where R ₁₂ and R _{13 are} independently selected from the group consisting of H, linear or branched hydrocarbon groups having a carbon chain containing from 1 to 10 carbon atoms,

or together with the atoms to which they are attached, can form a mono- or bicyclic ring containing from 5 to 14 ring elements,

where R ₁₄ selected from the group including:

- aliphatic ring systems;

- unsubstituted or substituted monocyclic aliphatic heterocycles;

- unsubstituted or substituted heteroaryl radical and

- unsubstituted or substituted phenyl group;

- group of the formula

где t равно 1 или 2

where t is 1 or 2

wherein R _'14 represents an unsubstituted or substituted phenyl group; where each of R ₇ -R _{11 is} independently selected from the group consisting of -H, NO ₂ , halogen, -O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OPh, —OBn, —Ph, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —O- (C ₁ -C ₆ ) alkyl , - (C = O) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups; or any pharmaceutically acceptable salt thereof,

and preferably a compound of formula I,

in which Z is selected from the group consisting of N and CR ₂₂ , where R ₂₂ is H or a bond with D;

in which D is selected from the group consisting of a bond, C = O and linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, where the carbon chain optionally contains ether (-O-) or thioether (-S -) bridge,

in which R _{1 is} selected from the group consisting of: triazolyl, imidazolyl, pyrimidinyl radical,

where each of R ₂ -R _{6 is} independently selected from the group consisting of —H, NO ₂ , halogen, —CN,

-N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ] and - (CH ₂ ) _0-1 R ₁₄ ,

or two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring,

where at least one of R ₂ —R ₆ is —CN,

where (i) at least one of R ₂ -R ₆ is - (CH ₂ ) _0-1 R ₁₄ , or

(ii) at least one of R ₂ —R ₆ is —N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ], or

(iii) at least two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring, or

where R ₁₂ and R _{13 are} independently selected from the group consisting of H, linear or branched hydrocarbon groups having a carbon chain containing from 1 to 10 carbon atoms,

or together with the atoms to which they are attached, can form a mono- or bicyclic ring containing from 5 to 14 ring elements,

where R ₁₄ selected from the group including:

- aliphatic ring systems;

- unsubstituted or substituted monocyclic aliphatic heterocycles;

- unsubstituted or substituted heteroaryl radical and

- unsubstituted or substituted phenyl group;

where each of R ₇ -R _{11 is} independently selected from the group consisting of -H, NO ₂ , halogen, -O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, -CN, -OH, -OPh, -OBn, -Ph, -OSO ₂ NR ₁₅ R _16, -SO ₂ R _26, -SO ₂ NR ₂₇ R _28, -O- (C ₁ -C ₆₎ alkyl , - (C = O) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups; or any pharmaceutically acceptable salt thereof.

One object of the present invention is the use of a compound for the preparation of a medicament for inhibiting aromatase activity and optionally for inhibiting STS activity, wherein the compound is described by formula I

in which Z is selected from the group consisting of N and CR ₂₂ , where R ₂₂ is H or a bond with D;

in which D is selected from the group consisting of a bond, C = O and linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, where the carbon chain optionally contains an oxy group (= O), ether (-0-) or a simple thioether (-S-) bridge,

in which R _{1 is} selected from the group consisting of: triazolyl, imidazolyl, pyrimidinyl radical,

where each of R ₂ —R _{6 is} independently selected from the group consisting of —H, —CN, NO ₂ , halogen,

-N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ] and - (CH ₂ ) _0-1 R ₁₄ ,

or two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring,

wherein at least one of R ₂ -R ₆ is -CN,

where (i) at least one of R ₂ -R ₆ is - (CH ₂ ) _0-1 R ₁₄ , or

(ii) at least one of R ₂ -R ₆ represents _{-N [(C = O) 0-1} R _{12] [(C = O) 0-1} R _13], or

(iii) at least two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring, or

(iv) at least one of R ₂ —R ₆ is - (CH ₂ ) _0-1 —O-R ′ ₁₄ ,

where R ₁₂ and R _{13 are} independently selected from the group consisting of H, linear or branched hydrocarbon groups having a carbon chain containing from 1 to 10 carbon atoms,

or together with the atoms to which they are attached, can form a mono- or bicyclic ring containing from 5 to 14 ring elements,

where R ₁₄ selected from the group including:

- aliphatic ring systems;

- unsubstituted or substituted monocyclic aliphatic heterocycles;

- unsubstituted or substituted heteroaryl radical and

- unsubstituted or substituted phenyl group;

- group of the formula

где t равно 1 или 2

where t is 1 or 2

wherein R _'14 represents an unsubstituted or substituted phenyl group;

where each of R ₇ -R _{11 is} independently selected from the group consisting of -H, NO ₂ , halogen, -O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OPh, —OBn, —Ph, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —O- (C ₁ -C ₆ ) alkyl ,

- (C = O) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups; or any pharmaceutically acceptable salt thereof,

and preferably a compound of formula I,

in which Z is selected from the group consisting of N and CR ₂₂ , where R ₂₂ is H or a bond with D;

in which D is selected from the group consisting of a bond, C = O and linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, where the carbon chain optionally contains ether (-O-) or thioether (-S -) bridge,

in which R _{1 is} selected from the group consisting of: triazolyl, imidazolyl, pyrimidinyl radical,

where each of R ₂ -R _{6 is} independently selected from the group consisting of —H, NO ₂ , halogen, —CN,

-N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ] and - (CH ₂ ) _0-1 R ₁₄ ,

or two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring,

where at least one of R ₂ —R ₆ is —CN,

where (i) at least one of R ₂ -R ₆ is - (CH ₂ ) _0-1 R ₁₄ , or

(ii) at least one of R ₂ —R ₆ is —N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ], or

(iii) at least two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring, or

wherein R ₁₂ and R ₁₃ are independently selected from the group consisting of H, linear or branched hydrocarbon group having a carbon chain containing from 1 to 10 carbon atoms,

or together with the atoms to which they are attached, can form a mono- or bicyclic ring containing from 5 to 14 ring elements,

where R ₁₄ selected from the group including:

- aliphatic ring systems;

- unsubstituted or substituted monocyclic aliphatic heterocycles;

- unsubstituted or substituted heteroaryl radical and

- unsubstituted or substituted phenyl group;

where each of R ₇ -R _{11 is} independently selected from the group consisting of -H, NO ₂ , halogen, -O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OPh, —OBn, —Ph, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —O- (C ₁ -C ₆ ) alkyl , - (C = O) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups; or any pharmaceutically acceptable salt thereof.

Also included within the scope of the present invention are new compounds of the present invention (such as those provided in the present invention), as well as methods for their preparation (such as the methods described in the present invention) as well as new intermediates (such as those provided in the present invention) intended for use in these methods.

For ease of use, these and other objects of the present invention will be discussed in sections with the corresponding names. However, the data provided in each section is not necessarily limited to each specific section.

SOME ADVANTAGES

One important advantage of the present invention is that the compounds of the present invention can act as STS inhibitors.

One important advantage of the present invention is that the compounds of the present invention can act as aromatase inhibitors.

One important advantage of the present invention is that the compounds of the present invention can act as STS inhibitors and aromatase inhibitors.

Another advantage of the compounds of the present invention is that they can be active in vivo.

Some of the compounds of the present invention may be non-estrogenic compounds. In the present invention, the term “non-estrogenic” means the absence or substantially the absence of estrogenic activity, such as defined in Protocol 4.

Another advantage is that some of the compounds may not be able, through metabolism, to turn into compounds that exhibit or induce hormonal activity.

Some of the compounds proposed in the present invention also have the advantage that they can be active when administered orally.

Some of the compounds of the present invention may be useful for the prevention and / or treatment of cancer, such as breast cancer, and (or alternatively) non-cancerous pathological conditions, such as the prevention and / or treatment of inflammatory pathological conditions, such as pathological conditions associated with any one or more of the following: autoimmune disorders, including, for example, rheumatoid arthritis, type I and II diabetes, systemic lupus erythematosus, multiple sclerosis, malignancy Twain gravis, vasculitis, ulcerative colitis and Crohn's disease, skin disorders, such as acne, psoriasis and contact dermatitis; transplant versus host reaction; eczema asthma and organ rejection after transplantation. The compounds of the present invention are particularly suitable when drugs are to be administered from an early age.

Thus, some of the compounds of the present invention are also contemplated to be used for the treatment of non-treatment of endocrine-dependent cancers, such as the treatment of autoimmune diseases.

The compounds of the present invention can also be used as an inducer of apoptosis.

The compounds of the present invention can also be used as cell growth inhibitors.

PREFERRED OBJECTS

As indicated in the present invention, the compound of formula I has the form

in which Z is selected from the group consisting of N and CR ₂₂ , where R ₂₂ is H or a bond with D;

in which D is selected from the group consisting of a bond, C = O and linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, where the carbon chain optionally contains an oxy group (= O), ether (-O-) or a simple thioether (-S-) bridge,

in which R _{1 is} selected from the group consisting of: triazolyl, imidazolyl, pyrimidinyl radical

where each of R ₂ —R _{6 is} independently selected from the group consisting of —H, —CN, NO ₂ , halogen,

-N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ] and - (CH ₂ ) _0-1 R ₁₄ ,

or two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring,

where at least one of R ₂ —R ₆ is —CN,

where (i) at least one of R ₂ -R ₆ is - (CH ₂ ) _0-1 R ₁₄ , or

(ii) at least one of R ₂ —R ₆ is —N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ], or

(iii) at least two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring, or

(iv) at least one of R ₂ —R ₆ is - (CH ₂ ) _0-1 —O-R ′ ₁₄ ,

wherein R ₁₂ and R ₁₃ are independently selected from the group consisting of H, linear or branched hydrocarbon group having a carbon chain containing from 1 to 10 carbon atoms,

or together with the atoms to which they are attached, can form a mono- or bicyclic ring containing from 5 to 14 ring elements,

where R ₁₄ selected from the group including:

- aliphatic ring systems;

- unsubstituted or substituted monocyclic aliphatic heterocycles;

- unsubstituted or substituted heteroaryl radical and

- unsubstituted or substituted phenyl group;

- group of the formula

где t равно 1 или 2

where t is 1 or 2

wherein R _'14 represents an unsubstituted or substituted phenyl group;

where each of R ₇ -R _{11 is} independently selected from the group consisting of -H, NO ₂ , halogen, -O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OPh, —OBn, —Ph, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —O- (C ₁ -C ₆ ) alkyl , - (C = O) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups or any pharmaceutically acceptable salt thereof, and preferably a compound of formula I,

in which Z is selected from the group consisting of N and CR ₂₂ , where R ₂₂ is H or a bond with D;

in which D is selected from the group consisting of a bond, C = O and linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, where the carbon chain optionally contains ether (-O-) or thioether (-S -) a bridge in which R _{1 is} selected from the group consisting of: triazolyl, imidazolyl, pyrimidinyl radical,

where each of R ₂ —R _{6 is} independently selected from the group consisting of —H, NO ₂ , halogen, —CN, —N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ] and - (CH ₂ ) _0-1 R ₁₄ ,

or two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring,

wherein at least one of R ₂ -R ₆ is -CN,

where (i) at least one of R ₂ -R ₆ is - (CH ₂ ) _0-1 R ₁₄ , or

(ii) at least one of R ₂ -R ₆ represents _{-N [(C = O) 0-1} R _{12] [(C = O) 0-1} R _13], or

(iii) at least two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring, or

wherein R ₁₂ and R ₁₃ are independently selected from the group consisting of H, linear or branched hydrocarbon group having a carbon chain containing from 1 to 10 carbon atoms,

or together with the atoms to which they are attached, can form a mono- or bicyclic ring containing from 5 to 14 ring elements,

where R ₁₄ selected from the group including:

- aliphatic ring systems;

- unsubstituted or substituted monocyclic aliphatic heterocycles;

- unsubstituted or substituted heteroaryl radical and

- unsubstituted or substituted phenyl group;

where each of R ₇ -R _{11 is} independently selected from the group consisting of -H, NO ₂ , halogen, -O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, -CN, -OH, -OPh, -OBn, -Ph, -OSO ₂ NR ₁₅ R _16, -SO ₂ R _26, -SO ₂ NR ₂₇ R _28, -O- (C ₁ -C ₆₎ alkyl , - (C = O) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups; or any pharmaceutically acceptable salt thereof.

One of ordinary skill in the art should understand that if D is a bond, then Z is attached directly to the adjacent ring. Thus, in this object, the compound is described by the formula

It should be understood that if Z is N, then the compound is described by formula Ia

It should be understood that if Z is CH, then the compound is described by formula Ib

It should be understood that if Z is CR ₂₂ and R ₂₂ is a bond with D, in which D is selected from the group consisting of straight or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, where the carbon chain optionally contains an oxy group (= O), ether (-O-) or thioether (-S-) bridge, the compound is described by formula Ic

One skilled in the art should understand that if R ₂₂ is a bond with D, then D must be selected from the group consisting of straight or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, where the carbon chain optionally contains an oxy group (= O), an ether (-O-) or a simple thioether (-S-) bridge. If R ₂₂ represents a bond with D, then D itself cannot denote a bond or C = O. The carbon chain containing an oxy group (= O) can be illustrated by the following radicals: —C (O) —CH ₂ -, —CH ₂ —C (O) —CH ₂ -, —C (O) —CH ₂ —CH ₂ - .

In one preferred aspect, D is selected from the group consisting of a bond and linear hydrocarbon groups containing a carbon chain containing from 1 to 6 carbon atoms.

Preferably, if D is selected from the group comprising a bond, C = O and - (CH ₂ ) _n -, where n is from 1 to 6, where - (CH ₂ ) ₂ - may contain an oxy group (= O), ether ( -O-) or a simple thioether (-S-) bridge. Preferably, if D is selected from the group consisting of a bond, C = O and - (CH ₂ ) _n -, where n is from 1 to 6, where - (CH ₂ ) _n - may contain ether (-O-) or simple thioether (-S-) bridge. Preferably, if D is selected from the group consisting of a bond, C = O and - (CH ₂ ) _n -, where n is from 1 to 6, where - (CH ₂ ) _n - may contain an oxy group (= O). More preferably, if D is selected from the group consisting of a bond, C = O and - (CH ₂ ) _n - where n is 1, 2 or 3, where - (CH ₂ ) _n - may contain ether (-O-) or simple thioether (-S-) bridge. More preferably, if D is selected from the group consisting of - (CH ₂ ) _n -, where n is 1, 2 or 3, where - (CH ₂ ) _n - may contain an oxy group (= O). More preferably, if D is - (CH ₂ ) _n -, where n is 1, 2 or 3. More preferably, if D is selected from the group consisting of a bond, C = O and - (CH ₂ ) _n -, where n is 1 or 2, where - (CH ₂ ) _n - may contain a simple ether (-O-) or simple thioether (-S-) bridge. More preferably, D is - (CH _{2) n} -, wherein n is 1 or 2.

Preferably, if D is selected from the group comprising a bond, C = O and —CH ₂ -. Preferably, if D is selected from the group consisting of —C (O) —CH ₂ —CH ₂ -, —CH ₂ —CH ₂ -, and —CH ₂ -. More preferably, if D is —CH ₂ -.

As indicated in the present invention, in formula I and in each of the other formulas described in the present invention, R _{1 is} preferably selected from the group including

where - - - denotes the position of accession.

As indicated in the present invention, in formula I and in each of the other formulas described in the present invention, R _{1 is} more preferably selected from the group consisting of

где - - - обозначает положение присоединения

where - - - indicates the position of accession

As indicated in the present invention, in formula I and in each of the other formulas described in the present invention, R ₁ more preferably means

где - - - обозначает положение присоединения

where - - - indicates the position of accession

Thus, these objects are compounds of formulas

In a preferred aspect, the compound is described by formula II or formula III

and preferably formula II.

In another aspect, preferred compounds are described by formula V

formula Va

and formula VI

As indicated in the present invention, each of R ₂ —R _{6 is} independently selected from the group consisting of —H, —CN, NO ₂ , halogen, —N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ] and - (CH ₂ ) _0-1 R ₁₄ , or two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring where at least one of R ₂ -R ₆ represents —CN. In one preferred aspect, each of R ₂ —R _{6 is} independently selected from the group consisting of —H, NO ₂ , —Cl, —CN, —N [(C = O) _0-1 R ₁₂ ] [(C = O) _{0 -1} R ₁₃ ] and - (CH ₂ ) _0-1 R ₁₄ . In another preferred aspect, each of R ₂ —R _{6 is} independently selected from the group consisting of —H, —CN, —N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ] and - (CH ₂ ) _0-1 R ₁₄ . In one aspect, at least one of R ₂ —R ₆ is —N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ]. In one aspect, at least one of R ₂ -R ₆ is - (CH ₂ ) _0-1 R ₁₄ . In one object, at least two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring.

In an object in which two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring, it is preferable if said ring is condensed with a phenyl ring and contains from 5 to 6 ring elements and where are additional ring elements that are non-phenyl ring elements selected from the group consisting of: = C (R ₃₂ ) -, -CR ₃₃ R ₃₄ -, -C (O) -, -O-, -S-, -N (R ₃₅ ) -, and = N-; where each of R ₃₂ -R ₃₅ independently means H or C ₁ -C ₆ alkyl.

Any of R ₂ -R ₆ may be denoted by the desired —CN. In one aspect, R ₂ is —CN. In one aspect, R ₃ is —CN. In one aspect, R ₄ is —CN. In one aspect, R ₅ is —CN. In one aspect, R ₆ is —CN. Preferably R ₄ is —CN.

In this object, preferably each of R ₂ —R _{6 is} independently selected from the group consisting of —H, —CN, NO ₂ , halogen, —N [(C = O) _0-1 R ₁₂ ] [(C = O) _{0- 1} R ₁₃ ] and - (CH ₂ ) _0-1 R ₁₄ , or two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached form a ring, where the ring system formed by two adjacent R ₂ -R groups ₆ , together with the carbon atoms to which they are attached, is selected from among 5- or 6-membered rings, where the ring contains a carbon atom and optionally one or more O, N and S.

More preferably, each of R ₂ —R _{6 is} independently selected from the group consisting of —H, —CN, NO ₂ , halogen, —N [(C = O) _0-1 R ₁₂ ] [(C = O) _{0- 1} R ₁₃ ], - (CH ₂ ) _0-1 R and ring systems formed by two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached, where the ring system formed by two adjacent R ₂ -R ₆ groups together with the carbon atoms to which they are attached, selected from the group including

where - - - denotes the position of the attachment of these two R ₂ -R ₆ and R ₂₄ selected from the group comprising H and linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms. Even more preferably, if each of R ₂ —R _{6 is} independently selected from the group consisting of —H, —CN, NO ₂ , halogen, —NR ₁₂ R ₁₃ , - (CH ₂ ) _0-1 R _14, and ring systems, formed by two of R ₂ -R ₆ , where these two R ₂ -R ₆ together with the phenyl ring to which they are condensed form a group selected from the group consisting of naphthyl, benzofuranyl and benzotriazolyl.

In another preferred aspect, R ₂ —R _{6 is} independently selected from the group consisting of —H, —CN, NO ₂ , halogen, —N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ] and - (CH ₂ ) _0-1 R ₁₄ , and more preferably, if each of R ₂ —R _{6 is} independently selected from the group consisting of —H, —CN, NO ₂ , halogen, —NR ₁₂ R ₁₃ , - (CH ₂ ) _0-1 R ₁₄ .

Any of R ₂ -R ₆ may represent a group - (CH ₂ ) _0-1 R ₁₄ . In one aspect, R ₂ represents a group - (CH ₂ ) _0-1 R ₁₄ . In one aspect, R ₃ is a group - (CH ₂ ) _0-1 R ₁₄ . In one aspect, R ₄ represents a group - (CH ₂ ) _0-1 R ₁₄ . In one aspect, R ₅ represents a group - (CH ₂ ) _0-1 R ₁₄ . In one aspect, R ₆ is a group - (CH ₂ ) _0-1 R ₁₄ . Preferably, if R ₃ denotes a group - (CH ₂ ) _0-1 R ₁₄ .

The group - (CH _{2) 0-1} R ₁₄ may or may not contain a fragment _CH2. Thus, in one object, the group is —R ₁₄ . In another aspect, the group is —CH ₂ R ₁₄ . In one preferred aspect, the CH ₂ moiety is contained only if R ₁₄ is unsubstituted phenyl or monocyclic aliphatic heterocycles selected from heterocycles containing at least a nitrogen atom and from 4 to 6 ring elements. In one preferred aspect, the CH ₂ moiety is contained only if R _{14 is} selected from the group consisting of substituted or unsubstituted phenyl, cyclic amine, piperazine, morpholine, lactam, pyrrolidinedione, azetidine, 1,3-diazetidine, 1,3-oxazetidine, 1, 3-piperazine, 1,3-oxazinane and piperidinedione groups. In one preferred aspect, a CH ₂ moiety is contained only if R _{14 is} selected from the group consisting of

где n равно 1, 2 или 3.

where n is 1, 2 or 3.

In one preferred aspect, a CH ₂ moiety is contained only if R ₁₄ is a phenyl group. In this object, the CH ₂ R ₁₄ group forms a benzyl group (which may be substituted or unsubstituted).

In one preferred aspect, R ₃ is a group - (CH ₂ ) _0-1 R ₁₄ and R ₄ is —CN. In another preferred aspect, R ₃ is —N [(C = O) _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ] and R ₄ is —CN.

In one preferred aspect, R ₂ —R _{6 is} independently selected from the group consisting of —H, —CN, - (CH ₂ ) _0-1 R ₁₄

In one preferred aspect, R ₂ and R ₅ are H. In another preferred aspect, R ₂ , R ₅ and R ₆ are N.

In one preferred aspect, R ₂ , R ₅ and R ₆ are H and R ₄ is —CN.

The group R _{14 is} selected from the group consisting of aliphatic ring systems, unsubstituted or substituted monocyclic aliphatic heterocycles; unsubstituted or substituted heteroaryl radical; and unsubstituted or substituted phenyl group. In one aspect, R ₁₄ is an aliphatic ring system. The aliphatic ring system R ₁₄ includes C ₃ -C ₁₂ cycloalkyl, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cycloalkenyl, such as cyclohexenyl. In one aspect, R ₁₄ is an unsubstituted or substituted monocyclic aliphatic heterocycle. The aliphatic heterocycle R ₁₄ includes an aliphatic ring, saturated or unsaturated, and containing at least one heteroatom selected from the group consisting of N, O and S, such as pyrrolidine, imidazolidine, pyrazolidine, isothiazolidine, thiazolidine, isoxazolidine, oxazolidine, piperidine , morpholine, dihydrooxazole, dihydroimidazole, dihydrofuran, dihydrothiophene. In one aspect, R ₁₄ is an unsubstituted or substituted heteroaryl radical. The heteroaryl radical R ₁₄ is an aromatic radical formed by a fused ring or rings in which at least one ring contains one or more identical or different heteroatoms selected from the group consisting of sulfur, nitrogen or oxygen. The following radicals can be mentioned as examples of heteroaryl radicals: pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, quinolinyl, quinolinyl, quinolinyl, benzoxadiazolyl, carbazolyl, phenoxazinyl, thienopyridinyl, thienopyrazinyl, embossed, benzothienyl, furyl, benzofuryl, dihydrobenzofuryl, thioxanthenyl, pyranyl, benzopyranyl, dibenzopyrazinyl, acridinyl. In one preferred aspect, the CH ₂ moiety is contained only if R _{14 is} selected from the group consisting of substituted or unsubstituted phenyl, cyclic amine, piperazine, morpholine, lactam, pyrrolidinedione and piperidinedione groups. In one aspect, R ₁₄ is a group selected from the group consisting of

, которая может быть незамещенной или

which may be unsubstituted or

substituted and in which n is 1, 2 or 3.

In a preferred aspect, R ₁₄ is an unsubstituted or substituted phenyl group. The phenyl group may contain one or more identical or different substituents selected from the group consisting of: —CN, NO ₂ , halogen, (C ₁ –C ₆ ) haloalkyl, (C ₁ –C ₆ ) alkyl, —OH, —OSO ₂ NR ₁₅ R ₁₆ , -SO ₂ NR ₂₇ R ₂₈ , aryl, aryloxy group, arylalkyloxy group, -O (C ₁ -C ₆ ) alkyl, -O- (C ₁ -C ₆ ) haloalkyl, -C (O) -OR ₃₁ , -NR ₄₁ R ₄₂ ; -SO ₂ -R ₂₆ and - (C = O) _0-1 NR ₂₉ R ₃₀ ; each of R ₃₁ , R ₄₁ and R _{42 is} independently selected from the group consisting of H and (C ₁ -C ₆ ) alkyl, R _{26 is} selected from the group consisting of a hydrocarbon radical or a radical of the formula —NR ₄₁ R ₄₂ . A preferred unsubstituted or substituted phenyl group for an unsubstituted or substituted phenyl group for R _{14 is} described by the formula

where - - - denotes the position of attachment and each of R ₁₇ -R _{21 is} independently selected from the group consisting of -H, NO ₂ , halogen, -O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OPh, —OBn, —Ph, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —O (C ₁ -C ₆ ) alkyl, - (C = O) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more sludge heteroatoms and groups.

The group R ′ ₁₄ represents an unsubstituted or substituted phenyl group. The group R ′ ₁₄ may be unsubstituted or the phenyl group may contain one or more substituents selected from the group consisting of —H, NO ₂ , halogen, —O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —O (C ₁ -C ₆ ) alkyl, and more preferably —O (C ₁ -C ₆ ) alkyl. In a preferred aspect, - (CH ₂ ) _0-1 —O — R ′ ₁₄ , represents —O-R ′ ₁₄ .

The term “hydrocarbon group” as used in the present invention means any alkyl group, alkenyl group, alkynyl group or acyl group, which may be linear, branched or cyclic, or an aryl group. The term "hydrocarbon" also includes these groups, which optionally may be substituted. If the hydrocarbon has a branched structure containing a substituent (s), then the substitution can take place along the main hydrocarbon chain or branching; alternatively, substituents may be in the main hydrocarbon chain and in branching.

In one preferred embodiment, the hydrocarbon group is an oxycarbon group.

In the present invention, the term “hydroxy hydrocarbon” means any alkoxy group, oxyalkenyl group, oxyalkynyl group, which may be linear, branched or cyclic, or an oxyaryl group. The term “hydroxy hydrocarbon” also includes these groups, which optionally may be substituted. If hydroxyhydrocarbon has a branched structure containing a substituent (s), then the substitution can take place along the main hydrocarbon chain or branching; alternatively, substituents may be in the main hydrocarbon chain and in branching.

Preferably, if the hydroxy hydrocarbon group is an alkoxy group. Preferably, the hydroxy hydrocarbon group is described by the formula —O— (C ₁ -C ₆ ) alkyl, such as —O- (C ₁ -C ₆ ) alkyl.

Preferably, if the hydrocarbon group is an alkyl group, particularly preferably (C ₁ -C ₆ ) alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and other isomers pentyl, and n-hexyl and other hexyl isomers. Preferably, the alkyl group is (C ₁ -C ₃ ) alkyl. Preferably, the alkyl group is methyl or ethyl, particularly preferably methyl.

In one preferred aspect, each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) cycloalkyl, (C ₁ -C ₆ ) alkenyl, (C ₁ - C ₆ ) acyl and (C ₁ -C ₆ ) aryl or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups.

In a preferred aspect, the group —O— (C ₁ -C ₆ ) haloalkyl is selected from the group consisting of —OCF ₃ and —OCF ₂ CF ₃ .

A preferred aliphatic ring system for R ₁₄ is an aliphatic ring containing from 3 to 11 carbon atoms. These rings may optionally contain one or more of the following substituents: NO ₂ , halogen, —O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, -OH, -OPh, -OBn, -Ph, -OSO ₂ NR ₁₅ R ₁₆ , -SO ₂ R ₂₆ , -SO ₂ NR ₂₇ R ₂₈ , -O- (C ₁ -C ₆ ) alkyl, - (C = O) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups. Preferably, if these rings may optionally contain one or more of the following substituents: —NO ₂ , (CH ₂ ) _0-6 CF ₃ , (C ₁ -C ₆ ) alkyl, —CN, —OH, —F, —Cl, -Br, -I and -O- (C ₁ -C ₆ ) alkyl. Particularly preferred groups are

where - - - denotes the position of attachment, and optionally containing one or more of the following substituents: NO ₂ , halogen, -O- (C ₁ -C ₆ ) halogenated, (C ₁ -C ₆ ) halogenated, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OPh, —OBn, —Ph, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —O- (C ₁ -C ₆ ) alkyl, - (C = O) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups. Preferably, if these rings may optionally contain one or more of the following substituents: —NO ₂ , (CH ₂ ) _0-6 CF ₃ , (C ₁ -C ₆ ) alkyl, —CN, —OH, —F, —Cl, -Br, -I and -O- (C ₁ -C ₆ ) alkyl.

A more preferred aliphatic ring system for R ₁₄ is a cycloalkyl group containing from 3 to 6 carbon atoms. Particularly preferred cycloalkyl groups are

where - - - denotes the position of attachment, and optionally containing one or more of the following substituents: NO ₂ , halogen, -O- (C ₁ -C ₆ ) halogenated, (C ₁ -C ₆ ) halogenated, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OPh, —OBn, —Ph, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —O- (C ₁ -C ₆ ) alkyl, - (C = O) _0-1 R ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups. Preferably, if these rings may optionally contain one or more of the following substituents: —NO ₂ , (CH ₂ ) _0-6 CF ₃ , (C ₁ -C ₆ ) alkyl, —CN, —OH, —F, —Cl, -Br, -I and -O- (C ₁ -C ₆ ) alkyl.

A preferred monocyclic aliphatic heterocycle for R ₁₄ is a ring containing 5 or 6 elements and containing a carbon atom and one of S, O and N. The ring may optionally contain the following substituents: NO ₂ , oxo group, halogen, -O- (C ₁ - C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OPh, —OBn, —Ph, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , -SO ₂ NR ₂₇ R ₂₈ , -O- (C ₁ -C ₆ ) alkyl, - (C = O) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups. Preferably, if these rings may optionally contain one or more of the following substituents: —NO ₂ , (CH ₂ ) _0-6 CF ₃ , (C ₁ -C ₆ ) alkyl, —CN, —OH, —F, —Cl, -Br, -I and -O- (C ₁ -C ₆ ) alkyl. A preferred monocyclic aliphatic heterocycle for R _{14 is} selected from the group consisting of

optionally containing one or more of the following substituents: NO ₂ , halogen, —O— (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, -OPh, -OBn, -Ph, -OSO ₂ NR ₁₅ R _16, -SO ₂ R _26, -SO ₂ NR ₂₇ R _28, -O- (C ₁ -C ₆₎ alkyl, - (C = O) _{0 -1} NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups. Preferably, if these rings may optionally contain one or more of the following substituents: —NO ₂ , (CH ₂ ) _0-6 CF ₃ , (C ₁ -C ₆ ) alkyl, —CN, —OH, —F, —Cl, -Br, -I and -O- (C ₁ -C ₆ ) alkyl, where R _{25 is} selected from the group consisting of H and linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, where R _{29 is} selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroato mov or groups. A preferred monocyclic aliphatic heterocycle for R _{14 is} selected from the group consisting of piperazine, morpholine, dihydrooxazole and dihydroimidazole, each of which is optionally substituted. A particularly preferred monocyclic aliphatic heterocycle for R _{14 is} selected from the group consisting of

Preferably, if R ₂₉ is H. If R ₂₉ is alkyl, then those values are preferred when R _{29 is} independently selected from the group consisting of lower. alkyl groups containing from 1 to 6 carbon atoms, i.e. methyl, ethyl, propyl and the like. R ₂₉ may be methyl. If R ₂₉ is aryl, typical values are phenyl, naphthyl and tolyl, such as m-tolyl, p-tolyl or o-tolyl. If R ₂₉ is cycloalkyl, then typical values are cyclopropyl, cyclopentyl, cyclohexyl and the like. The meanings of alkyl, cycloalkyl, alkenyl, acyl and aryl include substituted groups containing one or more groups as substituents that do not interfere with the inhibitory activity of the compound in relation to sulfatase. Typical non-interfering substituents include hydroxy group, amino group, halogen, alkoxy group, alkyl and aryl. A preferred heteroaryl for R ₁₄ is selected from the group consisting of furan, benzofuran, thiophene, oxazole and pyridine. A preferred heteroaryl for R _{14 is} selected from the group consisting of

A particularly preferred heteroaryl for R _{14 is} selected from the group consisting of

These rings may contain one or more of the following substituents: NO ₂ , halogen, —O— (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, - OH, -OPh, -OBn, -Ph, -OSO ₂ NR ₁₅ R ₁₆ , -SO ₂ R ₂₆ , -SO ₂ NR ₂₇ R ₂₈ , -O- (C ₁ -C ₆ ) alkyl, - (C = O ) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups. Preferably, if these rings may optionally contain one or more of the following substituents: —NO ₂ , (CH ₂ ) _0-6 CF ₃ , (C ₁ -C ₆ ) alkyl, —CN, —OH, —F, —Cl, -Br, -I and -O- (C ₁ -C ₆ ) alkyl, where R _{25 is} selected from the group consisting of H and linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, where R _{29 is} selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms s or groups.

A preferred heteroaryl for R ₁₄ is one of the monocyclic heterocycles described herein containing a phenyl ring fused to it. A particularly preferred heteroaryl for R ₁₄ is

optionally containing one or more of the following substituents: NO ₂ , halogen, —O— (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, -OPh, -OBn, -Ph, -OSO ₂ NR ₁₅ R ₁₆ , -SO ₂ R ₂₆ , -SO ₂ NR ₂₇ R ₂₈ , -O- (C ₁ -C ₆ ) alkyl, - (C = O) _{0 -1} NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups. Preferably optionally containing one or more of the following substituents: —NO ₂ , (CH ₂ ) _0-6 CF ₃ , (C ₁ –C ₆ ) alkyl, —CN, —OH, —F, —Cl, —Br, —I and —O— (C ₁ -C ₆ ) alkyl.

As should be understood from these descriptions, in a preferred aspect, the group R _{14 is} selected from the group consisting of:

(i) a group

wherein each of R ₁₇ -R ₂₁ are independently selected from the group consisting of H, NO _2, halo, -O- (C ₁ -C ₆₎ haloalkyl, (C ₁ -C ₆₎ haloalkyl, (C ₁ -C ₆₎ alkyl, —CN, —OH, —OPh, —OBn, —Ph, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —O- (C ₁ -C ₆ ) alkyl , - (C = 0) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups.

(ii) groups

where - - - denotes an attachment position, optionally containing one or more of the following substituents: NO ₂ , halogen, -O- (C ₁ -C ₆ ) halogenated, (C ₁ -C ₆ ) halogenated, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OPh, —OBn, —Ph, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —O- (C ₁ -C ₆ ) alkyl , - (C = O) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups.

(iii) groups

optionally containing one or more of the following substituents: NO ₂ , halogen, —O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, -OPh, -OBn, -Ph, -OSO ₂ NR ₁₅ R ₁₆ , -SO ₂ R ₂₆ , -SO ₂ NR ₂₇ R ₂₈ , -O- (C ₁ -C ₆ ) alkyl, - (C = O) _{0 -1} NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more sludge heteroatoms and groups.

(iv) a group

optionally containing one or more of the following substituents: NO ₂ , halogen, —O— (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, -OPh, -OBn, -Ph, -OSO ₂ NR ₁₅ R ₁₆ , -SO ₂ R ₂₆ , -SO ₂ NR ₂₇ R ₂₈ , -O- (C ₁ -C ₆ ) alkyl, - (C = O) _{0 -1} NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups.

In a preferred aspect, the group R ₁₄ is

where each of R ₁₇ —R _{21 is} independently selected from the group consisting of —H, NO ₂ , halogen, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , and —O— (C ₁ -C ₆ ) alkyl; where R ₂₆ , R ₂₇ and R _{28 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, and more preferably where each of R ₁₇ —R _{21 is} independently selected from the group consisting of —H, NO ₂ , halogen, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , and - O- (C ₁ -C ₆ ) alkyl; and R ₂₆ , R ₂₇ and R _{28 are} independently selected from the group consisting of H and alkyl.

In a more preferred aspect, the group R ₁₄ is

where each of R ₁₇ , R ₁₈ , R ₂₀ and R ₂₁ are —H and R _{19 is} selected from the group consisting of —O— (C ₁ -C ₆ ) alkyl, benzyloxy, —OH, —CN, —F, - ( CH ₂ ) _0-6 CF ₃ and OSO ₂ NH ₂ .

As indicated in the present invention, R ₁₂ and R _{13 are} independently selected from the group consisting of H, linear or branched hydrocarbon groups having a carbon chain containing from 1 to 10 carbon atoms, or together with the atoms to which they are attached can form mono - or a bicyclic ring containing from 5 to 14 ring elements.

Preferably, R ₁₂ and R _{13 are} independently selected from the group consisting of H, linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, or together with the atoms to which they are attached can form a mono- or bicyclic ring, containing from 5 to 10 ring elements. Preferably, R ₁₂ and R _{13 are} independently selected from the group consisting of H, linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, or together with the atoms to which they are attached can form a mono- or bicyclic ring, containing 5 or 6 ring elements.

; где каждый из R₃₆-R₃₉ независимо обозначает Н или С₁-С₆ алкил.In an object in which R ₁₂ and R ₁₃ together with the atoms to which they are attached form a mono- or bicyclic ring containing from 5 to 14 ring elements, preferably, if the ring elements of a mono- or bicyclic ring are selected from the group consisting of: = C (R ₃₆ ) -, -CR ₃₇ R ₃₈ -, -O-, = N-, -N (R ₃₉ ) - and

; where each of R ₃₆ -R ₃₉ independently represents H or C ₁ -C ₆ alkyl.

In one facility

- R ₁₂ and R _{13 are} independently selected from the group consisting of H, linear or branched hydrocarbon groups having a carbon chain containing from 1 to 10 carbon atoms, or together with the atoms to which they are attached can form a mono- or bicyclic ring, containing from 5 to 14 ring elements, or

- R ₁₂ and R _{13 are} independently selected from the group consisting of H, linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, or together with the atoms to which they are attached can form a mono- or bicyclic ring, containing from 5 to 10 ring elements, or

- R ₁₂ and R _{13 are} independently selected from the group consisting of H, linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms, or together with the atoms to which they are attached can form a mono- or bicyclic ring, containing 5 or 6 ring elements, or

- R ₁₂ and R ₁₃ together with the atoms to which they are attached can form a mono- or bicyclic ring containing 5 or 6 ring elements.

One of ordinary skill in the art should understand that if R ₁₂ and R ₁₃ together with the atoms to which they are attached can form a mono- or bicyclic ring, the group —N [(C = O) _0-1 R ₁₂ ] [( C = O) _0-1 R ₁₃ ] is included in the ring. Thus, in this object, if R ₁₂ and R ₁₃ together with the atoms to which they are attached can form a mono- or bicyclic ring, then the ring can be any ring in which the functional group —N [(C = O) is included _0-1 R ₁₂ ] [(C = O) _0-1 R ₁₃ ]. In this preferred aspect, R ₁₂ and R _13, together with the atoms to which they are attached, can form

where --- denotes the position of attachment and R ₂₃ selected from the group comprising H and linear or branched hydrocarbon groups having a carbon chain containing from 1 to 6 carbon atoms.

In a particularly preferred aspect, R _{3 is} selected from the group consisting of

(i) a group

where each of R ₁₇ -R _{21 is} independently selected from the group consisting of -H, NO ₂ , halogen, -O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OPh, —OBn, —Ph, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —O- (C ₁ -C ₆ ) alkyl , - (C = O) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more sludge heteroatoms and groups.

(ii) groups

where --- denotes an attachment position, optionally containing one or more of the following substituents: NO ₂ , halogen, —O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OPh, —OBn, —Ph, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —O- (C ₁ -C ₆ ) alkyl , - (C = O) _0-1 NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups

(iii) groups

optionally containing one or more of the following substituents: NO ₂ , halogen, —O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, -OPh, -OBn, -Ph, -OSO ₂ NR ₁₅ R ₁₆ , -SO ₂ R ₂₆ , -SO ₂ NR ₂₇ R ₂₈ , -O- (C ₁ -C ₆ ) alkyl, - (C = O) _{0 -1} NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups;

and

(iv) a group

optionally containing one or more of the following substituents: NO ₂ , halogen, —O— (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, -OPh, -OBn, -Ph, -OSO ₂ NR ₁₅ R ₁₆ , -SO ₂ R ₂₆ , -SO ₂ NR ₂₇ R ₂₈ , -O- (C ₁ -C ₆ ) alkyl, - (C = O) _{0 -1} NR ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups.

In a preferred aspect, R ₃ is

where each of R ₁₇ —R _{21 is} independently selected from the group consisting of —H, NO ₂ , halogen, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , and —O— (C ₁ -C ₆ ) alkyl;

where R ₂₆ , R ₂₇ and R _{28 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl.

In an even more preferred aspect, R ₃ is

where each of R ₁₇ —R _{21 is} independently selected from the group consisting of —H, NO ₂ , (CH ₂ ) _0-6 CF ₃ , (C ₁ -C ₆ ) alkyl, —CN, —OH, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —F, —Cl, —Br, —I and —O— (C ₁ -C ₆ ) alkyl.

In a preferred aspect, R ₃ is

wherein each of R ₁₇ —R _{21 is} independently selected from the group consisting of —H, halogen, (C ₁ -C ₆ ) haloalkyl, —OSO ₂ NH ₂ and —O- (C ₁ -C ₆ ) alkyl.

In one preferred aspect, R ₃ is

where each of R ₁₇ —R ₂₁ is —H.

In one preferred aspect, R ₁₄ is an unsubstituted heteroaryl group, and more preferably heteroaryl selected from the group consisting of furyl, thienyl and benzofuryl.

In one preferred aspect, R ₁₄ is a monocyclic aliphatic heterocycle and more preferably a monocyclic aliphatic heterocycle selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine or azepane, each of which is optionally substituted with an oxo group or (C ₁ -C ₆ ) alkyl.

In one preferred aspect, the group R ′ ₁₄ is an unsubstituted phenyl group. In another preferred aspect, R ′ ₁₄ is a phenyl group containing one or more substituents selected from the group consisting of —H, NO ₂ , halogen, —O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, —CN, —OH, —O (C ₁ -C ₆ ) alkyl, and more preferably —O (C ₁ -C ₆ ) alkyl. In a preferred aspect, - (CH ₂ ) _0-1 —O — R ′ ₁₄ , represents —O-R ′ ₁₄ .

In one preferred aspect, R ₁₄ is

where t is 1 or 2. Preferably, t is 1.

As indicated in the present invention, each of R ₇ -R _{11 is} independently selected from the group consisting of —H, NO ₂ , halogen, —O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkyl, -CN, -OH, -OPh, -OBn, -Ph, -OSO ₂ NR ₁₅ R ₁₆ , -SO ₂ R ₂₆ , -SO ₂ NR ₂₇ R ₂₈ , -O- (C ₁ -C ₆ ) alkyl, - (C = O) _0-1 R ₂₉ R ₃₀ and -CO (O) _0-1 R ₃₁ ;

where R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups where each of R ₂₆ -R _{31 is} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms and and groups. Preferably, each of R ₇ -R _{11 is} independently selected from the group consisting of —H, (C ₁ -C ₆ ) alkyl, —OH, —OSO ₂ NR ₁₅ R ₁₆ , —F, —Cl, —Br and —I . Preferably, at least one of R ₇ —R _{11 is} selected from the group consisting of —F, —Cl, —Br, and —I. Preferably, at least one of R ₇ -R ₁₁ is C ₁ -C ₃ alkyl. Preferably, at least one of R ₇ —R ₁₁ is —OSO ₂ NR ₁₅ R ₁₆ . In one particularly preferred aspect, at least one of R ₇ —R _{11 is} selected from the group consisting of —F, —Cl, —Br, and —I and at least one of R ₇ —R ₁₁ is —OSO ₂ NR ₁₅ R ₁₆ .

In one preferred aspect, R ₇ and R ₁₁ are —F. In another preferred aspect, R _{8 is} selected from the group consisting of —F, —Cl, —Br, and —I. In another preferred aspect, R ₉ is —OH, —OSO ₂ NH ₂ or —Br. In another preferred aspect, R ₉ is —OH or —OSO ₂ NH ₂ , and preferably R ₉ is —OSO ₂ NH ₂ .

In the —OSO ₂ group, NR ₁₅ R ₁₆ R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups. Preferably, at least one of R ₁₅ and R ₁₆ is H. Preferably R ₁₅ is H and R ₁₆ is H. It should be understood that “combinations” of H, alkyl, cycloalkyl, alkenyl, acyl, and aryl mean two or more groups combined. An example of such a combination is an arylalkyl group.

The term "acyl" as used in the present invention includes any group of the formula - (C = O) -alkyl. Preferred acyl groups are - (C = O) - (C ₁ -C ₂₀ ) alkyl, - (C = O) - (C ₁ -C ₁₀ ) alkyl, - (C = O) - (C ₁ -C ₆ ) alkyl, - (C = O) - (C ₁ -C ₃ ) alkyl and - (C = O) -CH ₃ . These preferred values in each case relate to the acyl used in the present invention, and, in particular, to R ₁₅ , R ₁₆ and each of R ₂₆ -R ₃₁ .

In the group —SO ₂ R ₂₆ R _{26 is} selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups. Preferably, R ₂₆ is H. If R ₂₆ is alkyl, then those values are preferred when R _{26 is} independently selected from the group consisting of lower. alkyl groups containing from 1 to 6 carbon atoms, i.e. methyl, ethyl, propyl and the like. R ₂₆ may be methyl. If R ₂₆ is aryl, typical values are phenyl, naphthyl and tolyl such as m-tolyl, p-tolyl or o-tolyl. If R ₂₆ is cycloalkyl, then typical values are cyclopropyl, cyclopentyl, cyclohexyl and the like. The meanings of alkyl, cycloalkyl, alkenyl, acyl and aryl include substituted groups containing one or more groups as substituents that do not interfere with the inhibitory activity of the compound in relation to sulfatase. Typical non-interfering substituents include hydroxy group, amino group, halogen, alkoxy group, alkyl and aryl.

In the —SO ₂ group, NR ₂₇ R ₂₈ R ₂₇ and R _{28 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups. Preferably, at least one of R ₂₇ and R ₂₈ is H. Preferably R ₂₇ is H and R ₂₈ is H. Being substituted, the N-substituted compounds of the present invention may contain 1 or 2 N-alkyl, N-alkenyl, N-cycloalkyl or N-aryl substituents, preferably containing or all containing a maximum of 10 carbon atoms. If R ₂₇ and / or R ₂₈ is alkyl, then those values are preferred when R ₂₇ and R _{28 are} all independently selected from the group consisting of lower. alkyl groups containing from 1 to 6 carbon atoms, preferably lower. branched or linear alkyl groups containing from 1 to 6 carbon atoms, i.e. methyl, ethyl, propyl, isopropyl and the like. R ₂₇ and R ₂₈ can both be methyl. If R ₂₇ and / or R ₂₈ is aryl, typical values are phenyl and tolyl, such as m-tolyl, p-tolyl or o-tolyl. If R ₂₇ and R ₂₈ are cycloalkyl, then typical values are cyclopropyl, cyclopentyl, cyclohexyl and the like. When combined, R ₂₇ and R ₂₈ usually form an alkylene group with the formation of a chain containing from 4 to 6 carbon atoms, optionally including one or more heteroatoms or groups, for example, form a 5-membered heterocycle, for example, a morpholine group, a pyrrolidine group or piperidine a group. The meanings of alkyl, cycloalkyl, alkenyl, acyl and aryl include substituted groups containing one or more groups as substituents that do not interfere with the inhibitory activity of the compound in relation to sulfatase. Typical non-interfering substituents include hydroxy group, amino group, halogen, alkoxy group, alkyl and aryl.

In one particularly preferred aspect, R ₉ is —OSO ₂ NR ₁₅ R ₁₆ . Preferably, if R ₁₅ and R _{16 are} independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or together are alkylene, where one or each alkyl or cycloalkyl or alkenyl optionally contains one or more heteroatoms or groups.

The term "sulfamate" as used in the present invention includes a sulfamic acid ester, or an ester of an N-substituted sulfamic acid derivative, or a salt thereof.

If the compound contains a sulfamate group, then the compound of the present invention is called sulfamate.

Being substituted, the N-substituted compounds of the present invention may contain 1 or 2 N-alkyl, N-alkenyl, N-cycloalkyl or N-aryl substituents containing or all containing a maximum of 10 carbon atoms. If R ₁₅ and / or R ₁₆ is alkyl, then those values are preferred when R ₁₅ and R _{16 are} all independently selected from the group consisting of lower. alkyl groups containing from 1 to 6 carbon atoms, i.e. methyl, ethyl, propyl and the like. R ₁₅ and R ₁₆ can both be methyl. If R ₁₅ and / or R ₁₆ is aryl, typical values are phenyl and tolyl, such as m-tolyl, p-tolyl or o-tolyl. If R ₁₅ and R ₁₆ are cycloalkyl, then typical values are cyclopropyl, cyclopentyl, cyclohexyl and the like. When combined, R ₁₅ and R ₁₆ usually form an alkylene group to form a chain containing from 4 to 6 carbon atoms, optionally including one or more heteroatoms or groups, for example, form a 5-membered heterocycle, for example, a morpholine group, a pyrrolidine group or piperidine a group.

The meanings of alkyl, cycloalkyl, alkenyl, acyl and aryl include substituted groups containing one or more groups as substituents that do not interfere with the inhibitory activity of the compound in relation to sulfatase. Typical non-interfering substituents include hydroxy group, amino group, halogen, alkoxy group, alkyl and aryl.

In some preferred embodiments, at least one of R ₁₅ and R ₁₆ is H.

In some other preferred embodiments, each of R ₁₅ and R ₁₆ is H.

In one particularly preferred aspect, the compound is described by formula VII

where each of R ₁₇ -R _{21 is} independently selected from the group consisting of —H, —CN, —OH, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —F, —Cl , -Br, -I and -O- (C ₁ -C ₆ ) alkyl.

In one particularly preferred aspect, the compound is described by formula VIII

where each of R ₁₇ -R _{21 is} independently selected from the group consisting of —H, —CN, —OH, —OSO ₂ NR ₁₅ R ₁₆ , —SO ₂ R ₂₆ , —SO ₂ NR ₂₇ R ₂₈ , —F, —Cl , -Br, -I and -O- (C ₁ -C ₆ ) alkyl.

In a particularly preferred aspect, the compound is selected from among the compounds of the formulas:

OTHER OBJECTS

Also included within the scope of the present invention are new intermediates that are useful in the preparation of the compounds of the present invention. For example, new precursor alcohols of the compounds are within the scope of the present invention. As another example, bis-protected compound precursors are included within the scope of the present invention. Examples of each of these precursors are provided in the present invention. Also included within the scope of the present invention is a process comprising either or both of these precursors, synthesizing the compounds of the invention.

The present invention also relates to

- the compound described in the present invention, intended for use in medicine;

- a pharmaceutical composition containing a compound described in the present invention, optionally in admixture with a pharmaceutically acceptable carrier, diluent, excipient or excipient;

- the compound described in the present invention, intended for use for the treatment of a pathological condition or disease associated with STS and aromatase;

- the compound described in the present invention, intended for use to treat a pathological condition or disease associated with undesirable concentrations of STS and undesirable concentrations of aromatase;

- the compound described in the present invention, designed to inhibit the activity of STS and / or to inhibit the activity of aromatase;

- the compound described in the present invention, designed to inhibit aromatase activity;

- the compound described in the present invention, designed to inhibit the activity of STS;

- the compound described in the present invention, designed to inhibit the activity of STS and to inhibit the activity of aromatase;

- the compound described in the present invention, intended for the treatment of cancer;

- the use of the compounds described in the present invention, for the preparation of a medicinal product intended for use for the treatment of a pathological condition or disease associated with STS and aromatase;

- the use of the compounds described in the present invention, for the preparation of a medicinal product intended for use for the treatment of a pathological condition or disease associated with undesirable concentrations of STS and with undesirable concentrations of aromatase;

- the use of a compound described in the present invention for the preparation of a medicament for inhibiting STS activity and / or inhibiting aromatase activity;

- the use of a compound described in the present invention for the preparation of a medicament for inhibiting aromatase activity;

- the use of the compounds described in the present invention, for the preparation of a medicinal product intended to inhibit the activity of STS;

- the use of a compound described in the present invention for the preparation of a medicament for inhibiting STS activity and inhibiting aromatase activity;

- the use of the compounds described in the present invention, for the preparation of a medicinal product intended for the treatment of cancer;

- the use of a compound described in the present invention for the manufacture of a medicament for use in the treatment of a pathological condition or disease associated with STS and / or aromatase and / or cell cycle and / or apoptosis and / or cell growth;

- the use of the compounds described in the present invention, for the preparation of a medicinal product intended for use for the treatment of a pathological condition or disease associated with undesirable concentrations of STS and / or undesirable concentrations of aromatase, and / or cell cycle, and / or apoptosis, and / or cell growth.

STEROID SULFATASE

Steroid sulfatase - sometimes called steroid sulfate or steryl sulfate or, for short, "STS" - hydrolyzes various steroid sulfates, such as estronsulfate, dehydroepiandrosterone sulfate and cholesterol sulfate. For STS, the EU enzyme number is 3.1.6.2.

STS were cloned and expressed. See, for example, Stein et al (J. Biol. Chem. 264: 13865-13872 (1989)) and Yen et al (Cell 49: 443-454 (1987)).

STS is an enzyme that is involved in a number of pathological conditions.

For example, the researchers found that the complete absence of STS leads to ichthyosis. According to some researchers, STS deficiency prevails to some extent in Japan. The same researchers (Sakura et al, J Inherit Metab Dis 1997 Nov; 20 (6): 807-10) also reported that allergic diseases, such as bronchial asthma, allergic rhinitis or atopic dermatitis, may be associated with steroid sulfatase deficiency.

In addition to pathological conditions due to a complete lack of STS activity, increased STS activity can also lead to pathological conditions. For example, and as noted above, there is strong evidence in favor of the effect of STS on breast cancer growth and metastasis.

STS is also involved in other pathological conditions. For example, Le Roy et al (Behav Genet 1999 Mar; 29 (2): 131-6), found that there may be a genetic correlation between steroid sulfatase concentration and the onset of behavior change in mice. These authors concluded that sulfonation of steroids can be the main driving force of a complex system, including genes, for which it is shown that they participate in aggressive behavior due to mutagenesis.

STS INHIBITION

It is believed that some pathological conditions associated with STS activity are due to the conversion of inactive, sulfonated estrone to active, non-sulfonated estrone. In pathological conditions associated with STS activity, it is desirable to inhibit STS activity.

In the present invention, the term "inhibition" includes reducing and / or eliminating and / or masking and / or preventing the harmful effects of STS.

STS INHIBITOR

In some aspects of the present invention, the compound may act as an STS inhibitor.

The term “inhibitor” as used in the present invention as applied to a compound of the present invention, means a compound that can inhibit STS activity, for example, reduce and / or eliminate, and / or mask, and / or prevent the harmful effects of STS. An STS inhibitor may act as an antagonist.

The ability of compounds to inhibit estronsulfatase activity can be assessed using intact JEG3 choriocarcinoma cells or placental microsomes. In addition, an experimental animal model can be used. A detailed description of suitable research protocols is provided in the following sections. It should be noted that other methods can be used to determine STS activity and thereby STS inhibition. For example, the data given in WO-A-99/50453 may be indicated.

In one object, in some cases, the compound is additionally characterized in that if the sulfamate groups are replaced by a sulfate group to form sulfate, then sulfate will be a hydrolyzable enzyme with steroid sulfatase activity (E.C. 3.1.6.2), i.e. when incubated with steroid sulfonase EC 3.1.6.2 at pH 7.4 and 37 ° C.

In one preferred embodiment, if the sulfamate group of the compound is replaced by a sulfate group to form sulfate, then this sulfate will be a hydrolyzable enzyme having steroid sulfatase activity (E.C. 3.1.6.2) and when incubated with steroid sulfatease EC 3.1.6.2 at pH 7.4 and 37 ° C this will result in a Km value of less than 200 mmol, preferably less than 150 mmol, more preferably less than 100 mmol, more preferably less than 75 mmol, more preferably less than 50 mmol.

In a preferred embodiment, the compound of the present invention is not hydrolyzed by an enzyme having steroid sulfatase activity (E.C. 3.1.6.2).

In some cases, it is preferable that the compound of the present invention is characterized by at least about 100-fold selectivity for the target target (for example, STS and / or aromatase), preferably at least about 150-fold selectivity for the target target, preferably not less than about 200 times the selectivity for the target, preferably at least about 250 times the selectivity for the target, preferably at least about 300 times the selectivity with respect to the target, preferably at least about 350-fold selectivity with respect to the target.

It should be noted that the compound of the present invention, in addition to or alternatively to its ability to inhibit the activity of STS and / or aromatase, may have other useful characteristics.

OTHER DEPUTIES

The compound of the present invention may contain substituents other than those indicated in Formula I. For example, these other substituents may be one or more of the following: one or more sulfamate groups, one or more phosphonate groups, one or more thiophosphonate groups, one or more sulfonate groups, one or more sulfonamide groups, one or more halide groups, one or more o groups O, one or more hydroxy groups, one or more amino groups, one or more sulfur-containing groups, one or more hydrocarbyl groups, such as an oxyhydrocarbyl group.

STS ACTIVITY STUDY USING CANCER CELLS

(PROTOCOL 1)

Inhibition of steroid sulfatase activity in JEG3 cells

Steroid sulfatase activity was investigated in vitro using intact JEG3 choriocarcinoma cells. This cell line can be used to study the fight against the growth of human breast cancer cells. It has significant steroid sulfatase activity (Boivin et al., J. Med. Chem., 2000, 43: 4465-4478) and can be obtained from the American Type Culture Collection (ATCC).

Cells are kept in minimal essential medium (MES) containing 20 mM HEPES (N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid), 5% fetal bovine serum, 2 mM glutamine, non-essential amino acids and 0.075% sodium bicarbonate. The amount is up to 30 mattresses tissue culture area of 25 cm ² were plated approximately 1 × 10 ⁵ cells / mattress using the medium mentioned above. Cells are grown to a confluence of 80%, and the medium is replaced every third day.

The monolayers of intact JEG3 cells in tissue culture mattresses with an area of 25 cm ² (triple studies) are washed with Earl's balanced salt solution (SSRE) and incubated for 3-4 hours at 37 ° C with the addition of 5 pmoles (7 (105 decays / min) [ 6.7-3H] estrone-3-sulfate (specific activity is 60 Ci / mmol) in serum-free MES medium (2.5 ml) together with estrone-3-sulfamate (11 concentrations: 0; 1 fM; 0.01 pM ; 0.1 pM; 1 pM; 0.01 nM; 0.1 nM; 1 nM; 0.01 mm; 0.1 mm; 1 mm) After incubation, each matrix is cooled and the medium (1 ml) is pipetted into individual tubes containing [14C] stron (7 (103 decays / min) (specific activity equal to 97 Ci / mmol). The mixture was thoroughly shaken for 30 s with toluene (5 ml). Experiments show that> 90% [14C] is removed from the aqueous phase during this treatment estrone and <0.1% [3H] estrone-3-sulfate. A portion (2 ml) of the organic phase is taken, evaporated and the residue 3H and 14C are determined by scintillation spectrometry. The mass of hydrolyzed estrone-3-sulfate is calculated from the obtained content 3H (adjusted for the volumes of the medium and the organic phase used, and for extraction, I add t [14C] estrone) and specific activity of the substrate. Each series of experiments includes incubation of microsomes prepared from sulfatase-positive human placenta (positive control) and cell-free mattresses (to assess the apparent non-enzymatic hydrolysis of the substrate). The number of cell nuclei in each mattress is determined using a Coulter counter after processing cell monolayers with saponin. One mattress from each series is used to assess the state and viability of cell membranes by the exclusion method using trypan blue dye (Phillips, HJ (1973) In: Tissue culture and applications, [eds: Kruse, DF & Patterson, MK]; pp. 406 -408; Academic Press, New York).

Data on steroid sulfatase activity is expressed as the mean value of ± 1 CO (standard deviation) for the entire product (estrone + estradiol) formed during the incubation period (3-4 hours), calculated for 106 cells, and for values of statistical significance, in as a percentage reduction (inhibition) compared to values obtained by incubation without estrone-3-sulfamate. To study the statistical significance of the results using unpaired student t criterion.

STS ACTIVITY STUDY USING PLACENTAL MICROS

(PROTOCOL 2)

Inhibition of steroid sulfatase activity in placental microsomes

Sulfatase-positive human placenta taken after a normally completed pregnancy is finely cut with scissors and washed once with cold phosphate buffer (pH 7.4, 50 mM), then suspended in cold phosphate buffer (5 ml / (g tissue)). Homogenization is carried out in a homogenizer using 3 pulses with a duration of 10 each, carried out between them by cooling on ice for 2 minutes. Nuclei and cell debris are removed by centrifugation (4 ° C) at 2000g for 30 min and portions (2 ml) of the supernatant are stored at 20 ° C. The protein concentration in the supernatant is determined according to the method of Bradford (Anal. Biochem., 72, 248-254 (1976)).

Incubation (1 ml) is carried out using protein at a concentration of 100 mg / ml, a substrate at a concentration of 20 mM [6.7-3H] estrone-3-sulfate (specific activity is 60 Ci / mmol) and incubation is carried out in for 20 min at 37 ° C. If necessary, use 8 concentrations of compounds: 0 (ie control); 0.05 mM; 0.1 mM; 0.2 mM; 0.4 mM; 0.6 mM; 0.8 mM; 1.0 mM. After incubation, each sample is cooled and the medium (1 ml) is pipetted into separate tubes containing [14C] estrone (7 × 103 decays / min) (specific activity is 97 Ci / mmol). The mixture was thoroughly shaken for 30 with toluene (5 ml). Experiments show that during this treatment> 90% [14C] estrone and <0.1% [3H] estrone-3-sulfate are removed from the aqueous phase. A portion (2 ml) of the organic phase was taken, evaporated and the content of 3H and 14C in the residue was determined by scintillation spectrometry. The mass of hydrolyzed estrone-3-sulfate is calculated from the obtained 3H content (adjusted for the volumes of the medium and organic phase used and [14C] estrone added for extraction) and the specific activity of the substrate.

EXPERIMENTAL ANIMAL MODEL FOR STS ACTIVITY DETERMINATION

(PROTOCOL 3)

Inhibition of estronsulfatase activity in vivo

The compounds of the present invention can be investigated using an experimental animal model, in particular using rats with removed ovaries. In this model, compounds that are estrogenic stimulate uterine growth.

The compound (0.1 mg / kg / day for 5 days) was administered orally to rats, and only a diluent (propylene glycol) was administered to the other group of animals. At the end of the study, liver tissue samples were taken and the activity of estronsulfatase was determined using 3H estronsulfate as a substrate, as described previously (see PCT / GB95 / 02638).

EXPERIMENTAL ANIMAL MODEL FOR DETERMINING ESTROGENIC ACTIVITY

(PROTOCOL 4)

The compounds of the present invention can be investigated using an experimental animal model, in particular using rats with removed ovaries. In this model, compounds that are estrogenic stimulate uterine growth.

The compound (0.1 mg / kg / day for 5 days) was administered orally to rats, and only a diluent (propylene glycol) was administered to the other group of animals. At the end of the study, the uterus is separated and weighed and the results are presented as the ratio (uterine mass) / (total body weight) × 100.

Compounds that do not significantly affect uterine growth are not estrogenic.

BIOTECHNOLOGICAL STUDIES FOR STS ACTIVITY DETERMINATION

(PROTOCOL 5)

The ability of compounds to inhibit estronsulfatase activity can also be evaluated using amino acid sequences or nucleotide sequences encoding STS, or their active fragments, derivatives, homologues or variants, for example, using high-throughput screening.

Any one or more suitable targets, such as an amino acid sequence and / or a nucleotide sequence, can be used to identify an agent capable of modulating STS by various drug screening techniques. The target used in such a study should not contain solvent, be fixed on a solid substrate, connected to the surface of the cell or located inside the cell. You can explore the cessation of activity of the target or the formation of associated complexes of the target with the studied tool

The study conducted in the present invention may be a screening in which a variety of agents are examined. In one aspect, the research methodology of the present invention is high throughput screening.

Drug screening methodologies can be based on the method described in Geysen Publication, European Patent Application 84/03564, published September 13, 1984, Briefly, it synthesizes a large number of small peptide test compounds on a solid support, such as plastic rods or some other surfaces. Test peptide compounds are reacted with a suitable target or fragment thereof and washed. Associated systems are then recorded, for example, using appropriately adapted techniques well known in the art. The purified target can also be directly applied to plates for use in drug screening techniques. Alternatively, non-neutralizing antibodies can be used to capture the peptide and immobilize on a solid support.

The present invention also relates to the use of competitive drug screening studies in which non-neutralizing antibodies capable of specifically binding a target compete for binding to the target with the test compound.

Another screening technique is high throughput screening (CHD) of agents having a suitable affinity for substances, and it is based on the technique described in detail in WO 84/03564.

It is assumed that the research methods proposed in the present invention will be suitable for small-scale and large-scale screening of test compounds, as well as for quantitative studies.

In one preferred aspect, the present invention relates to a method for identifying agents of the formula (I) that selectively modulate STS.

RESEARCH FOR DETERMINATION OF AROMATASE ACTIVITY USING JEG3 CELLS

(PROTOCOL 6)

Aromatase activity was investigated using JEG3 choriocarcinoma cells obtained from ATCC. This cell line is characterized by significant aromatase activity and is widely used to study the control of human aromatase activity (Bhatnager et al., J. Steriod Biochem. Molec. Biol. 2001, 76: 199-202). Cells are kept in minimal essential medium (MES) containing 20 mM HEPES, 10% fetal bovine serum, 2 mM glutamine, non-essential amino acids, and 0.075% sodium bicarbonate. Monolayers of intact JEG3 cells (2.5 × 10 ⁶ cells) in tissue culture mattresses with an area of 25 cm ² (triple studies) are washed with Earl's balanced salt solution (SSRE) and incubated with [1β- ³ H] androstenedione (2-5 nM . During the aromatase reaction, ³ H ₂ O is released, the content of which can be quantified using a liquid scintillation spectrometer. This technique using ³ H ₂ O isolation is widely used to determine aromatase activity (Newton et al., J. Steriod Biochem. 1986.24: 1033-1039). The number of cell nuclei in each mattress is determined using a Coulter counter after processing cell monolayers with saponin.

Data on aromatase activity are expressed as the average value of ± 1 CO for the product formed during the incubation time (30 min) calculated for 10 ⁶ cells, and for values of statistical significance, expressed as a percentage reduction (inhibition) compared to values obtained by incubation without an aromatase inhibitor. To study the statistical significance of the results using unpaired student t criterion. IC ₅₀ values are calculated as the concentration of inhibitor required to inhibit aromatase activity by 50%.

EXPERIMENTAL ANIMAL MODELS FOR DETERMINING AROMATASE ACTIVITY

(PROTOCOL 7)

(i) Inhibition of estrogen synthesis induced by HFA

The ability of compounds to inhibit in vivo activity was studied by the method of studying the synthesis of estrogen induced by gonadotropin from serum of mare (HGF). To do this, female rats (250 g) are injected with HFA (200 ME, subcutaneously) by injection. After 72 hours, a diluent (propylene glycol) or test compounds at various doses were orally administered to rats. 2 hours after the introduction of a heart puncture (under anesthesia), blood samples are taken. For animals in control groups and groups treated with the drug, the estradiol content in the plasma is determined. The effectiveness of aromatase inhibition is determined by measuring plasma estradiol concentrations using radioimmunoassay. This technique has been widely used to determine the effectiveness of aromatase inhibitors in vivo (Wouters et al., J. Steriod Biochem., 1989, 32: 781-788).

(ii) Inhibition of androstenedione-stimulated uterine growth in rats with removed ovaries

In female rats (250 g), the ovaries are removed and animals are used to determine the effectiveness of the effect of aromatase inhibition on uterine growth stimulated by androstenedione. Administration of androstenedione (30 mg / kg / day) over a 2-week period leads to a significant increase in uterine growth in animals with removed ovaries. This increase in uterine growth is stimulated by estrogen, which is formed from the introduced androstenedione as a result of exposure to the aromatase enzyme. By administering the compounds in conjunction with androstenedione, the degree of inhibition of aromatase can be determined by determining the weight of the uterus in exposed and untreated animals.

TREATMENT

The compounds of the present invention can be used as therapeutic agents - i.e. apply for treatment.

The term “treatment” includes healing effects, relief effects, and prophylactic effects.

You can treat people or animals, preferably male animals or people such as men.

PHARMACEUTICAL COMPOSITIONS

One object of the present invention is a pharmaceutical composition which comprises a compound of the invention and optionally a pharmaceutically acceptable carrier, diluent or excipient (including combinations thereof).

The pharmaceutical compositions may be intended for human or animal use in medicine or veterinary medicine and usually contain one or more of any pharmaceutically acceptable diluents, carriers or excipients. Carriers or diluents suitable for use in treatment are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985). The choice of a pharmaceutical carrier, inert excipient or diluent can be made in accordance with the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may contain, as, or in addition to, a carrier, an inert excipient or diluent, any suitable binder (s), lubricant (s), suspending agent (s), coating agent (s), solubilizing agent (s) .

Preservatives, stabilizers, colorants and even flavoring agents may be included in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and p-hydroxybenzoic acid esters. Antioxidants and suspending agents may also be used.

Depending on the delivery system, various requirements may be imposed on the compositions / preparations. For example, the pharmaceutical composition of the present invention can be prepared for delivery using a mini pump or through the mucous membrane, for example, as a nasal spray or aerosol for inhalation or an oral solution, or for parenteral delivery, for which the composition is formulated intended for injection, for example, for intravenous, intramuscular or subcutaneous delivery. Alternatively, the preparation can be prepared for delivery in both ways.

If the product must be delivered through the mucous membrane of the gastrointestinal tract, it must remain stable when moving along the gastrointestinal tract, for example, it must be stable against proteolytic decomposition, stable in an acidic environment and resistant to the washing effect of bile.

When appropriate, the pharmaceutical compositions can be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or powder, by the use of a skin patch, orally in the form of tablets containing inert excipients such as starch or lactose or in capsules or in vaginal suppositories of an ovoid form individually or in a mixture with inert excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents, or they may be administered pa parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, the compositions are best used in the form of a sterile aqueous solution, which may contain other substances, for example, salts or monosaccharides, in an amount sufficient to make the solution isotonic with blood. For buccal or sublingual administration, compositions in the form of tablets or lozenges, which can be prepared according to conventional techniques, can be used.

COMBINED MEDICINE

The compound of the present invention can be used in combination with one or more other active agents, such as one or more other pharmaceutically active agents.

For example, the compounds of the present invention can be used in combination with other STS inhibitors and / or other inhibitors, such as an aromatase inhibitor (such as, for example, 4-hydroxyandrostenedione (4-OH)), and / or steroids, such as natural neurosteroids, dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PS) and / or other structurally similar organic compounds. Examples of other STS inhibitors can be found in the above publications.

In addition, or alternatively, the compound of the present invention can be used in combination with a biological response modifier.

The term “biological response modifier” (“MBO”) includes cytokines, immunomodulators, growth factors, hematopoiesis regulatory factors, colony stimulating factors, chemotactic, hemolytic and thrombolytic factors, cell surface receptors, ligands, molecules that provide white blood cell adhesion, monoclonal antibodies and therapeutic vaccines, hormones, extracellular matrix components, fibronectin, etc. For some applications, it is preferable if the biological response modifier is a cytokine. Examples of cytokines include: interleukins (IL) - such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10 , IL-11, IL-12, IL-19; tumor necrosis factor (TNF) - such as TNF-α; interferon alpha, beta and gamma; TGF-β. For some applications, it is preferred that the cytokine is tumor necrosis factor (TNF). In some applications, the TNF can be any type of TNF — such as TNF-α, TNF-β, including derivatives or mixtures thereof. More preferably, the cytokine is TNF-α. A description of TNF can be found in the art — for example, in WO-A-98/08870 and WO-A-98/13348.

INTRODUCTION

Typically, the doctor will determine the actual dosage, which is most suitable for a particular subject, and it will vary depending on the age, body weight and response of a particular patient. The following doses are typical for the average case. Of course, there may be individual cases where wider or narrower dose ranges should be used.

The compositions of the present invention can be administered by direct injection. The composition can be prepared for parenteral, mucosal, intramuscular, intravenous, subcutaneous, ocular or transdermal administration. If necessary, the agent can be administered in a dose equal to from 0.01 to 30 mg / (kg body weight), such as equal to from 0.1 to 10 mg / kg, more preferably from 0.1 to 1 mg / (kg body weight )

In particular, the funds proposed in the present invention, depending on the mode, you can enter from 1 to 4 times a day, preferably 1 or 2 times a day. The specific dose and frequency of administration for any particular patient may vary and depends on many factors, including the activity of the particular compound used, metabolic stability and duration of action of this compound, age, body weight, general health, gender, diet, route and time of administration, speed elimination, combination of drugs, the severity of a particular pathological condition and the recipient undergoing treatment.

In addition to the typical delivery routes — indicated above — the term “administration” also includes delivery by means of means such as lipid-mediated transfection, liposomes, immunoliposomes, lipofectin, cationic amphiphiles containing hydrophilic and hydrophobic groups on opposite sides (CFA) and combinations thereof. Delivery routes for such methods include, but are not limited to, through the mucous membrane, nasal, oral, parenteral, gastrointestinal, local or sublingual.

The term “administration” includes, but is not limited to, mucosal delivery, for example, in the form of a nasal spray or aerosol for inhalation or an oral solution, a parenteral route in which delivery is by injection, such as intravenous, intramuscular or subcutaneous .

Thus, for administration as a medicinal product, the STS inhibitors of the present invention can be prepared in any suitable manner using conventional pharmaceutical preparation techniques and pharmaceutical carriers, excipients, excipients, diluents, and the like. and usually for parenteral administration. Exemplary effective doses may range from 1 to 1000 mg / day, such as from 10 to 900 mg / day, or even from 100 to 800 mg / day, depending on the activity of the particular compounds used and for a patient with an average (70 kg) weight body. More suitable dosages for preferred and more active compounds are in the range of 200 to 800 mg / day, more preferably 200 to 500 mg / day, most preferably 200 to 250 mg / day. They can be administered in single dose modes, in divided dose modes and / or in multiple dose modes for several days. For oral administration, they can be prepared in the form of tablets, capsules, solution or suspension containing from 100 to 500 mg of the compound in a single dose. Alternatively and preferably, the compounds are prepared for parenteral administration in a vehicle suitable for parenteral administration in the form of single daily doses ranging from 200 to 800 mg, preferably from 200 to 500, more preferably from 200 to 250 mg. However, the value of such effective daily doses varies depending on the intrinsic activity of the active ingredient and the patient’s body weight and, based on their professional training, the appropriate decision is made by the attending physician.

CELL CYCLE

The compounds of the present invention can be used in a method for treating cell cycle disorders.

As noted in the publication "Molecular Cell Biology" 3rd Ed. Lodish et al. pages 177-181, different eukaryotic cells can grow and divide at completely different speeds. For example, yeast cells can divide every 120 minutes, and for the first division of embryonic cells in the fertilized eggs of sea urchins and insect eggs, it may take only 1530 minutes, since one large existing cell divides. However, it takes 10-20 hours to double the number of cells in most growing plants and animals, and the number of some doubles at a much lower rate. Many adult cells, such as nerve cells and striated muscle cells, do not divide at all; others, such as fibroblasts, which promote wound healing, grow when necessary, and otherwise do not divide.

Yet every eukaryotic cell that divides must be ready to transfer the same genetic material to two daughter cells. In eukaryotic cells, DNA synthesis does not occur during the cell division cycle, it occurs only during part of the cell cycle before division.

The relationship between eukaryotic DNA synthesis and cell division has been carefully analyzed in mammalian cell cultures, which are all capable of growth and division. It was found that, unlike bacteria, in eukaryotic cells only part of the time is spent on DNA synthesis and it ends 1 hour before cell division (mitosis). Thus, after DNA synthesis and before cell division, there is a period of time; another period of time was found after division and before the next cycle of DNA synthesis. This analysis led to the conclusion that the eukaryotic cell cycle contains phase M (mitosis), phase G ₁ (first time interval), phase S (DNA synthesis), phase G ₂ (second time interval) and re-phase M. Phases between mitoses (G ₁ , S and G ₂ ) are collectively called interphase.

Many non-dividing cells in tissues (for example, all non-dividing fibroblasts) suspend the cycle after mitosis and immediately before DNA synthesis; they say that such "resting" cells have left the cell cycle and are in a state of G ₀

When the cells are at one of the three stages of the cell cycle interphase, they can be identified from using a fluorescence activated cell sorter (FACS) and the relative DNA content can be determined in them: cells that are in state G ₁ (before DNA synthesis) contain a certain amount of x DNA in phase S (DNA replication), the content is from x to 2x; and in phase G ₂ (or M), contains 2x DNA.

The following stages of mitosis and cytokinesis occur in animal cells.

(a) Interphase. Stage G ₂ interphase immediately precedes the onset of mitosis. During phase S, the chromosomal DNAs replicate and bind to the protein, however, the chromosomes are not visible as separate structures. The nucleolus is the only nuclear substructure that is visible in an optical microscope. In a diploid cell before DNA replication there are two morphological chromosomes of each type and the cell is designated as 2n. In phase G ₂ after DNA replication, the cell is designated as 4n. There are 4 copies of each chromosomal DNA. Since the sister chromosomes are not yet separated from each other, they are called sister chromatids.

b) Early prophase. Centrioles, each together with the newly formed daughter centriole, begin to move towards the opposite poles of the cell; chromosomes can be seen as long strings. The nuclear membrane begins to separate into small vesicles.

(c) Medium and late prophase. Chromosome condensation is complete; the structure of each visible chromosome consists of two chromatids held together by their centromeres. Each chromatid contains 2 new replicated daughter DNA molecules. The microtubule of the spindle begins to expand from areas directly adjacent to the centrioles, which move closer to its poles. Some spindle fibers stretch from pole to pole; most go to chromatids and join kinetochores.

(d) Metaphase. Chromosomes move towards the equator of the cell, where they are located in the equatorial plane. Sister chromatids are not yet separated.

(e) Anaphase. These two sister chromatids are separated into independent chromosomes. Each contains a centromere, which, with the help of a spindle fiber, is connected to one pole to which it moves. Thus, one copy of each chromosome is transmitted to each sister cell. At the same time, the cells are elongated, as are the spindles going from pole to pole. Cytogenesis begins as soon as a cleavage groove begins to form.

(f) Telophase. New membranes form around daughter nuclei; chromosomes unwind and become less distinct, the nucleolus repeatedly becomes visible, and a nuclear membrane forms around each daughter nucleus. Cytokinesis is almost complete, and the spindle disappears as microtubules and other fibers are depolymerized. During mitosis, the "daughter" centriole at each pole grows to its full length. During telophase, the doubling of each of the starting centrioles is completed and new daughter centrioles will form during the subsequent interphase.

(g) Interphase. After completion of cytokinesis, the cells enter the G ₁ phase _{of the} cell cycle and the cycle repeats.

Keep in mind that the cell cycle is an extremely important cellular process. Deviations from the normal cell cycle can lead to a number of diseases of the internal organs. An extended and / or unlimited cell cycle can lead to cancer. An abbreviated cell cycle can lead to degenerative pathological conditions. The use of a compound of the present invention may provide a means of treating such disorders and pathological conditions.

Thus, the compound of the present invention may be suitable for use in the treatment of cell cycle disorders such as cancers, including hormone-dependent and hormone-independent cancers.

In addition, the compound of the present invention may be suitable for the treatment of cancers such as breast cancer, ovarian cancer, endometrial cancer, sarcoma, melanoma, prostate cancer, pancreatic cancer, and the like. and other solid tumors.

In some applications, the cell cycle inhibits and / or prevents its progress and / or stops, preferably if the progress of the cycle is prevented and / or stopped. In one object, the cell cycle can be inhibited and / or prevent its progression and / or stopped in the G ₂ / M phase. In one aspect, the course of the cell cycle can be irreversibly prevented and / or inhibited and / or stopped, preferably if the course of the cell cycle is irreversibly prevented and / or stopped.

The expression "irreversible prevention of leakage and / or inhibition and / or stopping" means that after application of the compound of the present invention, after the removal of the compound, the effect of the compound is still observed, namely, the prevention of leakage and / or inhibition and / or arrest of cellular cycle. More precisely, the expression "irreversible prevention of flow and / or inhibition and / or stop" means that when studied according to the cell cycle research protocol of the present invention, the cells treated with the test compound after stage 2 of protocol 7 show less growth than the control cells. A detailed description of the protocol is given below.

Thus, the present invention relates to compounds that: in vitro inhibit the growth of positive for the estrogen receptor (ER +) and negative for ER (ER-) breast cancer cells due to the prevention of leakage and / or inhibition, and / or stopping the cell cycle; and / or lead to regression of breast tumors caused by nitrosomethylurea (HMM) in intact animals (i.e., which have not undergone ovariectomy); and / or prevent the progression of the cell cycle and / or inhibit and / or stop the cycle in cancer cells; and / or act in vivo by preventing the onset and / or inhibition and / or stopping of the cell cycle and / or act as an agonist of the cell cycle.

CELL STUDY

(PROTOCOL 7)

Methodology

Stage 1

Breast cancer MCF-7 cells were plated in multi-well culture plates at a density of 10 ⁵ cells / well. The cells are allowed to adhere and grow to a fusion of approximately 30%, after which they are treated as follows:

Control - no processing

Test compound (ASC) 20 μM

Cells are grown for 6 days in a growth medium containing ASC, and the medium / ASC system is replaced every 3 days. At the end of this period, the number of cells is counted using a Coulter cell counter.

Stage 2 After treatment with ASC for 6 days, the cells are re-plated at a density of 10 cells / well. Additional processing is not carried out. Cells are allowed to grow for another 6 days in the presence of growth medium. At the end of this period, the number of cells is re-counted.

CANCER

As indicated above, the compounds of the present invention may be suitable for the treatment of cell cycle disorders. In particular, cancer is a violation of the cell cycle.

Cancer remains the leading cause of death in most Western countries. Previously developed cancer treatments include blocking the action or synthesis of hormones to inhibit the growth of hormone-dependent tumors. However, more aggressive chemotherapy is currently used to treat hormone-independent tumors.

Therefore, the main objective of therapy is the development of a drug intended for the anticancer treatment of hormone-dependent and / or hormone-independent tumors with the elimination of some or all of the side effects associated with chemotherapy.

After synthesis, estrogens are known to enter into a number of hydroxylation and conjugation reactions. Until now, it was believed that such reactions are part of a metabolic process that ultimately makes estrogens soluble in water and enhances their excretion from the body. It is now apparent that some hydroxy-containing metabolites (e.g., 2-hydroxy and 16-alpha-hydroxy) and conjugates (e.g., estronsulfate, E1S) are important for some of the complex effects that estrogens have in the body.

Researchers have studied the formation of 2- and 16-hydroxylated estrogens due to conditions that alter the risk of breast cancer. There is currently evidence that factors that increase 2-hydroxylase activity are associated with a reduced risk of cancer, while factors that enhance 16-alpha hydroxylation may increase the risk of breast cancer. Additional interest in the biological role of estrogen metabolites has been stimulated by an increasing body of evidence that 2-methoxyestradiol is an endogenous metabolite with antimitotic ability. 2-MeOE2 is formed from 2-hydroxyestradiol (2-OHE2) using catechol estrogen methyltransferase, an enzyme that is widespread in the body.

Researchers have shown that in vivo 2-MeOE2 inhibits the growth of a tumor resulting from subcutaneous injection of Met A sarcoma cells, melanoma B 16 or estrogen receptor-negative (ER-) MDA-MB-435 breast cancer. It also inhibits the proliferation and migration of endothelial cells and in vitro angiogenesis. It has been suggested that the ability of 2-MeOE2 to inhibit tumor growth in vivo may be due to its ability to suppress tumor-induced angiogenesis, rather than directly suppressing tumor cell proliferation.

The mechanism by which 2-MeOE2 has significant anti-mitogenic and anti-angiogenic effects is still being studied. There is evidence that, at high concentrations, it can inhibit microtubule polymerization and act as a weak inhibitor of colchicine binding to tubulin. However, it has recently been established that at concentrations that block mitosis, tubulin filaments in the cells do not depolymerize, but have a morphology identical to that found after treatment with taxol. Therefore, it is possible that, like taxol, a drug that is used to treat breast and ovarian cancer, 2-MeOE2 acts by stabilizing microtubule dynamics.

While the identification of 2-MeOE2 as a new cancer treatment is a significant success, the oral bioavailability of estrogens is low. In addition, they can undergo significant metabolism during the first passage through the liver. As part of a research program to develop a steroid sulfatase inhibitor for the treatment of breast cancer, estrone-3-O-sulfamate (EMATE) has been identified as an active site-specific inhibitor. It was unexpectedly found that EMATE has an active estrogenic ability, since its uterotropic activity in rats is 100 times higher than the activity of estradiol. Its increased estrogenicity is presumably due to the fact that it is adsorbed by red blood cells, which protect it from inactivation when passing through the liver and act as a reservoir for its slow release over an extended period of time. A variety of ring A analogs were synthesized and investigated, including 2-methoxyestron-3-O-sulfamate. Although this compound as active as a steroid sulfatase inhibitor is as active as EMATE, it does not show estrogenicity.

The compound of the present invention may be a treatment for cancer, and in particular breast cancer.

In addition to this or alternatively, the compound of the present invention can be used to block the growth of cancer, including leukemia and solid tumors, such as tumors of the breast, endometrium, prostate, ovary and pancreas.

ESTROGEN TREATMENT

Some of the compounds of the present invention may be useful for controlling estrogen levels in the body, especially in women. Thus, some of the compounds may be useful as fertilization control agents, such as an oral contraceptive pill, pill, solution or lozenge. Alternatively, the compound may be used as an implant or patch.

Thus, the compounds of the present invention may be useful in the treatment of hormonal pathological conditions associated with estrogen.

Additionally or alternatively, the compound of the present invention may be useful in the treatment of hormonal pathological conditions in addition to estrogen-related. Therefore, the compound of the present invention can also affect hormonal activity and can also affect the immune response.

NEURODEGENERATIVE DISEASES

The compounds of the present invention may be useful in the treatment of neurodegenerative diseases and similar pathological conditions.

For example, it is believed that STS inhibitors may be useful in improving memory function in patients suffering from diseases such as amnesia, head injuries, Alzheimer's disease, epileptic dementia, pre-dementia, post-traumatic dementia, senile dementia, multi-infarct dementia and dementia after or patients who, for another reason, need better memory.

TH1 (T-helpers 1)

Some of the compounds of the present invention can be used in connection with TH1.

For example, it is believed that the presence of STS inhibitors in macrophages or other antigen-containing cells may reduce the ability of sensitized T cells to elicit a TH1 response (high IL-2, IFNγ low in IL-4). Therefore, normal regulatory effects on other steroids such as glucocorticoids will prevail.

INFLAMMATORY PATHOLOGICAL CONDITIONS

Some of the compounds of the present invention may be useful in the treatment of inflammatory pathological conditions, such as pathological conditions associated with any one or more of the following: autoimmune disorders, including, for example, rheumatoid arthritis, type I and II diabetes, systemic red lupus, multiple sclerosis, malignant myasthenia gravis, vasculitis, ulcerative colitis and Crohn's disease, skin disorders, such as psoriasis and contact dermatitis; transplant versus host reaction; eczema asthma and organ rejection after transplantation.

For example, it is believed that STS inhibitors can prevent the normal physiological effects of DHEA or related steroids on immune and / or inflammatory responses.

The compounds of the present invention may be useful in the preparation of a medicament intended for endogenous glucocorticoid-like action.

OTHER TREATMENTS

It should also be understood that the compound / composition of the present invention can be used for treatment in other important cases.

For example, the compound or composition of the present invention can be used to treat the disorders listed in WO-A-99/52890 - namely:

In addition to this or alternatively, the compound or composition of the present invention can be used to treat the disorders listed in WO-A-98/05635. For ease of use, the following is part of this list: cancer, inflammation or inflammatory disease, skin disorder, fever, cardiovascular manifestations, hemorrhage, coagulation and acute phase reaction, cachexia, anorexia, acute infection, HIV infection (human immunodeficiency virus), shock conditions, graft versus host disease, autoimmune disease, reperfusion injury, meningitis, migraine and aspirin-dependent antithrombosis; tumor growth, invasion and spread, angiogenesis, metastases, malignant ascites and malignant pleural effusion; cerebral ischemia, coronary heart disease, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma, multiple sclerosis, neurodegeneration, Alzheimer's disease, atherosclerosis, stroke, vasculitis, Crohn's disease and ulcerative colitis; periodontitis, gingivitis; psoriasis, atopic dermatitis, chronic ulcers, bullous epidermolysis; corneal ulceration, retinopathy and surgical healing of wounds; rhinitis, allergic conjunctivitis, eczema, anaphylaxis; restenosis, congestive heart failure, endometriosis, atherosclerosis, or endosclerosis.

In addition to this or alternatively, the compound or composition of the present invention can be used to treat the disorders listed in WO-A-98/07859. For ease of use, the following is part of this list: cytokine activity and cell proliferation / differentiation; immunosuppressive or immunostimulating activity (for example, for the treatment of immunodeficiency, including infection with the human immunodeficiency virus; regulation of lymphocyte growth; for the treatment of cancer and many autoimmune diseases and to prevent transplant rejection or to give immunity to the tumor); regulation of hematopoiesis, for example, for the treatment of myeloid or lymphoid diseases; stimulating the growth of bone, cartilage, tendon, ligament and nervous tissue, for example, to heal wounds, to treat burns, ulcers and periodontal disease and neurodegeneration; inhibition or activation of follicle-stimulating hormone (modulation of fertility); chemotactic / chemokinetic activity (for example, to mobilize specific types of cells in areas of damage or infection); hemostatic and thrombolytic activity (for example, for the treatment of hemophilia and stroke); anti-inflammatory activity (for the treatment of, for example, septic shock or Crohn's disease); as antimicrobial agents; modulators, for example, metabolism or dynamics; as analgesics; for the treatment of specific deficiency disorders; for the treatment of, for example, psoriasis in medicine or veterinary medicine.

In addition to this, or alternatively, the composition of the present invention can be used to treat the disorders listed in WO-A-98/09985. For ease of use, the following is part of this list: activity in the inhibition of macrophages and / or T cells and thereby anti-inflammatory activity; anti-immune activity, i.e. an inhibitory effect on the cellular and / or humoral immune response, including a non-inflammatory response; inhibition of the ability of macrophages and T cells to adhere to the components of the extracellular matrix and fibronectin, as well as upregulating the expression of fas receptors in T cells; inhibition of an unwanted immune response and inflammation, including arthritis, including rheumatoid arthritis, inflammation associated with hypersensitivity, allergic reactions, asthma, systemic lupus erythematosus, collagen diseases and other autoimmune diseases, inflammation associated with atherosclerosis, atherosclerosis, atherosclerotic heart disease, reperfusion , cardiac arrest, myocardial infarction, inflammatory vascular disorders, respiratory distress syndrome or other cardiopulmonary diseases, inflammation peptic ulcer, ulcerative colitis and other diseases of the gastrointestinal tract, liver fibrosis, cirrhosis or other liver diseases, thyroiditis or other diseases of the glands, glomerulonephritis or other diseases of the kidneys and urinary tract, otitis media or other otolaryngological diseases, dermatitis or other skin diseases, periodontal diseases or other dental diseases, orchitis or epididymal orchitis, infertility, testicular injury or other testicular immune-related diseases, placental dysfunction ile, placental insufficiency, habitual miscarriage, eclampsia, preeclampsia and other gynecological diseases associated with the immune response and / or inflammation, posterior uveitis, intermediate uveitis, anterior uveitis, conjunctivitis, chorioretinitis, uveoretinitis, optic neuritis, intraocular inflammation, for example macular cystoid edema, sympathetic ophthalmia, scleritis, retinal pigment degeneration, immune and inflammatory components of the eye fundus degenerative disease, inflammatory components of herbs eyes, inflammation of the eye caused by an infection, proliferative vitreoretinopathies, acute ischemic optic neuropathy, excessive scarring, for example, after glaucoma surgery, an immune and / or inflammatory reaction to an ophthalmic implant, and other eye diseases associated with the immune response and inflammation, inflammation associated with autoimmune diseases or pathological conditions or disorders in which suppression of the immune response and / or inflammation of the central nervous system (CNS) is beneficial any other organ, Parkinson’s disease, complications and / or side effects caused by treatment of Parkinson’s disease, AIDS-related (acquired immunodeficiency syndrome) dementia complex, HIV-related encephalopathy, Devic’s disease, Sydenham’s chorea, Alzheimer's disease and other degenerative diseases, pathological conditions or CNS disorders, inflammatory components upon impact, post-polyiopia syndrome, immune and inflammatory components of mental disorders, myelitis, encephalitis, subacute sclerosing panencephalus , encephalomyelitis, acute neuropathy, subacute neuropathy, chronic neuropathy, Guillain-Barré syndrome, Sydenham chorea, malignant myasthenia gravis, pseudotumor brain tumor, Down syndrome, Huntington's disease, amyotrophic lateral sclerosis, inflammatory components of CNS compression or CNS trauma or CNS infection, infections components of atrophy and dystrophy of muscles and diseases associated with the immune response and inflammation, pathological conditions or disorders of the central and peripheral nervous system, post-traumatic inflammation, septic shock, infectious diseases, inflammatory complications or side effects after surgery, bone marrow transplantation or other complications and / or side effects after transplantation, inflammatory and / or immune complications and side effects of gene therapy, for example, due to infection by a virus carrier, or inflammation associated with AIDS, suppressing or inhibiting the humoral and / or cellular immune response, treating or alleviating the course of a monocytic or white blood cell proliferative diseases, for example, leukemia, by reducing the number of monocytes or lymphocytes, preventing and / or treating transplant rejection in case of transplantation of native or artificial cells, tissues or organs such as the cornea, bone marrow, lenses, pacemakers, native or artificial skin tissue .

GETTING COMPOUNDS

The compounds of the present invention can be prepared by reacting the corresponding alcohol with a suitable chloride. For example, the sulfamates of the present invention can be prepared by reacting the corresponding alcohol with a suitable sulfamoyl chloride of the formula R ¹⁵ R ¹⁶ NSO ₂ Cl.

Typical conditions for carrying out this reaction are as follows.

Sodium hydride and sulfamoyl chloride are added with stirring at 0 ° C to a solution of alcohol in anhydrous dimethylformamide. Then the reaction mixture was allowed to warm to room temperature, then stirring was continued for another 24 hours. The reaction mixture was poured into a cold saturated sodium bicarbonate solution and the resulting aqueous phase was extracted with dichloromethane. The combined organic extracts were dried over anhydrous MgSO ₄ . Filtration followed by evaporation of the solvent in vacuo and evaporation with toluene gives a crude residue, which is then purified by flash chromatography.

Preferably, the alcohol is suitably converted to a derivative prior to reaction with sulfamoyl chloride. If necessary, the functional groups of the alcohol can be protected by known methods and the protective group or groups removed at the end of the reaction.

Sulfamates are preferably prepared in accordance with the procedures described in Page et al (1990 Tetrahedron 46; 2059-2068).

Phosphonates can be prepared by appropriately combined procedures described in Page et al (1990 Tetrahedron 46; 2059-2068) and PCT / GB92 / 01586.

Sulfonates can be prepared according to appropriately modified procedures described in Page et al (1990 Tetrahedron 46; 2059-2068) and in PCT / GB92 / 01586.

Thiophosphonates can be prepared according to appropriately modified procedures described in Page et al (1990 Tetrahedron 46; 2059-2068) and in PCT / GB91 / 00270.

Preferred methods of preparation are also presented in the description below.

Summary

In summary, the present invention relates to new compounds intended for use as steroid sulfatase inhibitors and / or aromatase inhibitors and / or apoptosis modulators and / or cell cycle modulators and / or cell growth, and to pharmaceutical compositions containing them .

The compounds of the present invention can be prepared in accordance with the general synthesis schemes set forth below and in accordance with the preparation examples of the compounds of the present invention described below.

Scheme 1. General synthesis route for the preparation of derivatives containing substituted biphenyls.

Scheme 2. General synthesis route for the preparation of derivatives containing a 1-triazolyl or 1-imidazolyl group.

Scheme 3. General route of synthesis to obtain derivatives containing an aliphatic ring.

Scheme 4. General synthesis route for the preparation of derivatives containing a linear or branched alkyl group.

Scheme 5. General synthesis route for preparing derivatives containing a substituted biphenyl fragment in which Z = carbon atom and D = bond.

Scheme 6. General synthesis route for obtaining derivatives containing a substituted biphenyl fragment in which Z = carbon atom and D = (CH ₂ ) _n .

Scheme 7. General synthesis route for preparing derivatives in which R ₁ and R ₂ together with the adjacent phenyl ring form a fused bicyclic ring.

Scheme 8. General synthesis route for the preparation of derivatives in which R ₁ is a monocyclic or fused bicyclic heterocycle or pact.

Scheme 9. General synthesis route for preparing derivatives containing piperidine, morpholine, piperazine and a cyclic amine.

Scheme 10. General synthesis route for the preparation of derivatives containing 1H-pyrrolidione, pyrrolidinedione and piperidinedione.

EXAMPLES

Below the present invention will be described in more detail only by way of example with reference to the accompanying drawings, in which the following is presented:

Figure 1 presents the diagram.

Figure 2 presents the diagram.

Below, the present invention will be described by way of example only. However, it should be understood that the examples show the preferred compounds of the present invention, as well as preferred routes for their preparation and intermediates useful for their preparation.

Synthesis paths

The compounds of the present invention were synthesized according to synthetic routes and schemes.

4- (4H-1,2,4-Triazol-4-ylamino) -2-bromobenzonitrile (САВ05094)

To a solution of 4H-1,2,4-triazole-4-amine (4.204 g, 50.0 mmol) in DMSO (dimethyl sulfoxide) (50 ml) was added KOtBu (5.51 g, 50.0 mmol). The mixture was stirred at room temperature for 0.5 h, then 4-fluoro-2-bromobenzonitrile (5.00 g, 25.0 mmol) was added and stirring was continued for 1 h. The mixture was poured onto crushed ice and neutralized with a 2M KHSO solution ₄ . The precipitate was filtered off and recrystallized from MeOH to give CAB05094 (4.82 g, 73%) as a light yellow crystalline solid. t _square = 234-236 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.66 (dd, J = 8.6, 2.4 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 7 78 (d, J = 8.6 Hz, 1H), 8.86 (s, 2H), 10.45 (s, 1H); ¹³ C NMR (nuclear magnetic resonance) (100.6 MHz, DMSO-d ₆ ) δ 105.0, 111.5, 115.4, 117.8, 126.0, 136.2, 143.9, 151, 8; MCHR (low resolution mass spectrometry) (HIAD - (chemical ionization at atmospheric pressure)): m / z 261.8 (100%, [C ₉ H ₅ ⁷⁹ BrN ₅ ] ^- ), 263.8 (90%, [ C ₉ H ₅ ⁸¹ BrN ₅ ] ^- ); HRMS (high resolution mass spectrometry) (ER + (electrospray in positive ion mode)): calculated for C ₉ H ₇ ⁷⁹ BrN ₅ [M + H] ⁺ : 263.9879, found: 263.9870;

4 - ((4- (Benzyloxy) benzyl) (4H-1,2,4-triazol-4-yl) amino) -2-bromobenzonitrile (САВ05114)

To a solution of compound CAB05094 (1.32 g, 5.0 mmol) in DMF (N, N-dimethylformamide) (20 ml) was added NaH (0.200 g, 3.0 mmol, 60% in mineral oil) at room temperature. The mixture was stirred for 0.5 h, then benzyloxybenzyl chloride (1.16 g, 5.0 mmol) was added and stirring was continued for 18 h. The reaction mixture was diluted with EtOAc (50 ml), washed with water (3 (30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was recrystallized from 2-propanol to give CAV05114 (1.772 g, 77%) as colorless needles, mp = 210-212 ° C ; 1 H NMR (400 MHz, DMSO-d6) (4.99 (s, 2H), 5.06 (s, 2H), 6.65 (dd, J = 8.6, 2.4 Hz, 1H), 6.94 (AA'BB ', 2H), 7.15 (d, J = 2.4 Hz, 1H), 7.19 (AA'BB', 2H), 7.30-7.46 (m, 5H), 7.81 (d, J = 8.6 Hz, 1H), 8.73 (s, 2H); 13C NMR (100.6 MHz, DMS0-d6) (56.4, 69, 2, 105.5, 112.8, 114.8, 116.7, 117.6, 126.0, 126.1, 127.8, 127.9, 128.4, 130.2, 135.9, 136.9, 143.3, 152.3, 158.2; MSNR (ER +): m / z 460.1 (100%, [M + H] +); HRMS (ER +): calculated for C23H18BrN5ONa [ M + Na] +: 482.0587; Found: 482.0588; Analysis: Calculated for C23H18BrN5O: C, 60.01; H, 3.94; N, 15.21. Found: C, 60.1; H, 3.92; N, 15.3.

5 - ((4- (Benzyloxy) benzyl) (4H-1,2,4-triazol-4-yl) amino) biphenyl-2-carbonitrile (САВ06018)

A mixture of compound CAB05114 (1.56 g, 3.39 mmol), phenylboronic acid (0.61 g, 5.0 mmol), dimethoxyethane (25 ml) and a 2M solution of Na ₂ CO ₃ (25 ml) in a N ₂ atmosphere was boiled under reflux, then Pd ₂ (dba) ₂ (0.05 g, 0.055 mmol) was added. The mixture was kept at reflux for 4 h (the progress of the reaction was monitored by TLC (thin layer chromatography)), then it was cooled to room temperature and filtered (through celite) to remove solids. The mixture was then extracted with EtOAc (3 × 50 ml). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO ₂ , CHCl ₃ / acetone (4: 1)], then recrystallized from EtOAc / hexane to give CAB06018 (0.798 g, 51%) as colorless small crystals. t _square = 171-173 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.05 (s, 2H), 5.06 (s, 2H), 6.72 (dd, J = 9.0, 2.8 Hz, 1H) 6.80 (d, J = 2.8 Hz, 1H), 6.96 (AA'BB ', 2H), 7.23 (AA'BB', 2H), 7.30-7.53 (m , 10H); 7.86 (d, J = 9.0 Hz, 1H); 8.78 (s, 2H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 56.5, 69.2, 101.9, 112.7, 114.0, 114.8, 118.8, 126.6, 127.8 , 127.9, 128.5, 128.6, 128.8, 128.9, 130.1, 135.5, 136.9, 137.8, 143.4, 146.3, 151.5, 158 , 2; MCHR (ER +): m / z 458.4 (60%, [M + H] ⁺ ); 389.3 (100%); MCBP (ER +): calculated for C ₁₉ H ₂₄ N ₅ O [M + H] ⁺ : 458.1975, found: 458.1971; Analysis: Calculated for C ₂₉ H ₂₃ N ₅ O: C, 76.13; H, 5.07; N, 15.31. Found: C, 76.2; H, 5.07; N, 15.4.

5 - ((4-Hydroxybenzyl) (4H-1,2,4-triazol-4-yl) amino) biphenyl-2-carbonitrile (САВ06021)

To a solution of compound CAB06018 (0.458 g, 1.00 mmol) in THF (tetrahydrofuran) and MeOH was added Pd-C (0.05 g, 5% Pd). The mixture was stirred in an H2 atmosphere for 18 hours, then the catalyst was filtered off (through celite) and the volatiles were removed under reduced pressure. The residue was recrystallized from EtOAc to give CAB06021 (0.206 g, 56%) as a white solid. t _square > 180 ° C (with decomposition); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.98 (s, 2HO, 6.68 (AA'BB ', 2H), 6.70-6.82 (m, 2H), 7.06 ( AA'BB ', 2H), 7.45-7.54 (m, 5H), 7.86 (d, J = 8.6 Hz, 1H), 8.73 (s, 2H), 9.50 ( s, 1H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 56.6, 101.8, 112.7, 114.0, 115.4, 118.8, 124.4, 128, 6, 128.8, 128.9, 130.2, 135.5, 137.9, 143.5, 146.3, 151.6, 157.3; MCHR (ER +): m / z 368.2 (100%, [M + H] ⁺ ); MCBP (ER +): calculated for C ₂₂ H ₁₇ N ₅ O [M + H] ⁺ : 368.1506, found: 368.1499.

4 - (((6-Cyanobiphenyl-3-yl) (4H-1,2,4-triazol-4-yl) amino) methyl) phenyl sulfamate (САВ06025)

To a solution of sulfamoyl chloride (0.520 g, 4.5 mmol) in DMA (N, N-dimethylacetamide) (1 ml) at 0 ° C was added a solution of compound САВ06021 (0.146 g, 0.397 mmol) in DMA (5 ml). The solution was stirred at 0 ° C for 2 hours and at room temperature overnight. EtOAc (60 ml) and water (30 ml) were added, the organic layer was separated, washed with water (3 × 20 ml) and brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was recrystallized from EtOAc to give CAB06025 (0.132 g, 75%) as a white solid. t _square > 200 ° C (with decomposition); H NMR (400 MHz, DMSO-d ₆ ) δ 5.18 (s, 2H), 6.69 (dd, J = 8.6, 2.7 Hz, 1H), 6.77 (d, J = 2 , 7 Hz, 1H), 7.23 (AA'BB ', 2H), 7.42 (AA'BB', 2H), 7.46-7.55 (m, 5H), 7.87 (d, J = 8.6 Hz, 1H), 8.04 (s, 2H), 8.86 (s, 2H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 56.6, 102.0, 112.6, 113.9, 118.8, 122.3, 128.6, 128.8, 129.0 , 129.8, 133.3, 135.6, 137.8, 143.4, 146.4, 149.9, 151.4; MCHP (ER- (negative ion electrospray)): m / z 445.7 (100%, [M-H] ⁺ ); MCBP (ER +): calculated for C ₂₂ H ₁₉ N ₆ O ₃ S [M + H] ⁺ : 447.1234, found: 447.1223.

5-Fluorobiphenyl-2-carbonitrile (САВ06020)

A mixture of 2-bromo-4-fluorobenzonitrile (5.6 g, 28.0 mmol), phenylboronic acid (4.27 g, 35.0 mmol), dimethoxyethane (25 ml) and 2M Na ₂ CO ₃ solution (40 ml) refluxed, then Pd ₂ (dba) ₃ (0.10 g, 0.11 mmol) was added and heating continued for 5 hours. After cooling to room temperature, CHCl ₃ (50 ml) was added and the mixture was filtered (through celite) ) The mixture was extracted with EtOAc (3 × 50 ml). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO ₂ , CHCl ₃ / hexane (1:10)], then recrystallized from hexane to give CAB06020 (4.29 g, 78%) as colorless needles. t _square = 79-80 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.14 (dt, J = 8.6, 2.7 Hz, 1H), 7.22 (dd, J = 9.4, 2.7 Hz, 1H) 7.46-7.57 (m, 5H); 7.77 (dd, J = 8.6, 5.5 Hz, 1H); MCHR (ER +): m / z 197.9 (100%, [M + Hf); MCBP (ER +): calculated for C ₁₃ H ₉ FN [M + H] ⁺ : 198.0714, found: 198.0706; Analysis: Calculated for C ₁₃ H ₈ FN: C, 79.17; H, 4.09; N, 7.10. Found: C, 79.3; H, 4.08; N, 7.04.

5- (4H-1,2,4-Triazol-4-ylamino) biphenyl-2-carbonitrile (САВ06022)

To a solution of 4-amino-4H-1,2,4-triazole (3.29 g, 39.14 mmol) in DMSO (40 ml) was added KOtBu (4.39 g, 39.14 mmol). The mixture was stirred at room temperature for 0.5 h, then the CAV06020 compound (3.86 g, 19.57 mmol) was added and stirring was continued for 1 h. The mixture was poured onto crushed ice and neutralized with a 2M KHSO ₄ solution. The white precipitate was filtered off, washed with water and recrystallized from 2-propanol to give CAB06022 (3.62 g, 71%) as light yellow crystals. W = 181-182 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.51 (d, J = 2.5 Hz, 1H), 6.60 (dd, J = 8.5, 2.5 Hz, 1H), 7 42-7.58 (m, 5H); 7.81 (d, J = 8.5 Hz, 1H); 8.89 (s, 2H); 10.34 (s, 1H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) 8 101.3, 111.4, 112.6, 119.0, 128.4, 128.8, 128.9, 135.7, 137.8 144.1, 146.4, 150.9; MCHR (ER +): m / z 262.0 (100%, [M + H] ⁺ ); HRMS (ER +): calculated for C ₁₅ H ₁₁ N ₅ [M + H] ⁺ : 262.1087, found: 262.1080.

4-Benzyloxy-3-fluorobenzaldehyde (САВ06038).

A mixture of 3-fluoro-4-hydroxybenzaldehyde (4.264 g, 30.0 mmol), benzyl bromide (5.986 g, 35.0 mmol, 4.16 ml) and K ₂ CO ₃ (8.20 g, 59.0 mmol) in DMF (50 ml) was stirred at room temperature for 48 hours, then EtOAc (100 ml) and water (50 ml) were added. The organic layer was separated, washed with water (2 × 50 ml), brine (30 ml) and dried (Na ₂ SO ₄ ). Concentration in vacuo gave a white solid residue. Recrystallization from CH ₂ Cl ₂ / n-hexane gave CAB06038 as colorless needles (5.59 g, 81%). 1 mp. = 94-95 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.24 (s, 2H), 7.12 (dd, J = 8.2, 8.2 Hz, 1H), 7.34-7.48 (m, 5H), 7.59-7.66 (m, 2H), 9.85 (d, J = 2.0 Hz, 1H); MCHR (ER +): m / z 231.1 (100%, [M + H] ⁺ ).

(4- (Benzyloxy) -3-fluorophenyl) methanol (САВ06039).

To a solution of the CAV06038 compound (2.30 g, 10.0 mmol) in MeOH (10 ml) and THF (10 ml) at 0 ° C was added NaBH ₄ (0.20 g, 5.28 mmol). The mixture was stirred for 1 h, then EtOAc (50 ml) and water (20 ml) were added. The organic layer was separated, washed with 2M KHSO ₄ solution (30 ml) and brine (30 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography [5CiS, EtOAc / petroleum ether (1: 4)] to give CAB06038 (2.19 g, 94%) as a colorless crystalline solid. t _square = 56-57 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.71 (s, 1H exchange with D ₂ O), 4.61 (s, 2H), 5.15 (s, 2H), 6.97 (dd, J = 8.6, 8.6 Hz, 1H), 7.02 (dd, J = 8.6, 1.9 Hz, 1H), 7.13 (dd, J = 11.7 Hz, 1.9 Hz, 1H), 7.30-7.46 (m, 5H); MCHR (BBA + (fast atom bombardment)): m / z 232.1 (55%, [M] ⁺ ), 215.1 (40%), 91.1 (100%).

1- (Benzyloxy) -4- (chloromethyl) -2-fluorobenzene (САВ06040)

Thionyl chloride (2.0 ml) was added to a solution of compound CAB06039 (2.00 g, 8.61 mmol) in CH ₂ Cl ₂ (20 ml) at room temperature. The mixture was stirred at room temperature for 2 hours, then the solvents and excess thionyl chloride were removed under reduced pressure. The residue was purified by flash chromatography [SiO ₂ , CHCl ₃ ] to give a white solid, which was recrystallized from petroleum ether to give CAV06040 (2.01 g, 93%) as colorless fine needles. t _square = 67-69 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.52 (s, 2H), 5.15 (s, 2H), 6.96 (dd, J = 8.2, 8.2 Hz, 1H), 7 04-7.06 (m, 1H); 7.15 (dd, J = 11.7, 2.4 Hz, 1H); 7.31-7.45 (m, 5H); MCHP (FAB +): m / z 250.0 (16%, [M] ⁺ ), 215.0 (10%), 91.0 (100%).

5 - ((4- (Benzyloxy) -3-fluorobenzyl) (4H-1,2,4-triazol-4-yl) amino) biphenyl-2-carbonitrile (САВ06041)

To a solution of the CAV06022 compound (0.522 g, 1.99 mmol) in DMF (10 ml) was added NaH (0.080 g, 2.0 mmol) at room temperature. The mixture was stirred for 0.5 h until the evolution of hydrogen ceased, then CAB06040 (0.501 g, 2.0 mmol) was added and stirring was continued for 18 hours. The reaction mixture was diluted with EtOAc (50 ml), washed with water (3 × 30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO ₂ , CHCl ₃ / acetone (4: 1)] to give CAB06041 as a white solid (0.879 g, 92%), which was recrystallized from EtOAc / cyclohexane to give colorless small needles. t _square = 166-168 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.06 (s, 2H), 5.14 (s, 2H), 6.70 (dd, J = 8.6, 2.7 Hz, 1H), 6 79 (d, J = 2.7 Hz, 1H), 7.01-7.06 (m, 1H), 7.15-7.20 (m, 1H), 7.24 (dd, J = 12 1, 2.3 Hz, 1H), 7.32-7.45 (m, 5H), 7.47-7.55 (m, 5H), 7.86 (d, J = 8.6 Hz, 1H), 8.83 (s, 2H); MCHR (ER +): m / z 476.3 (100%, [M + H] ⁺ ); HRMS (ER +): calculated for C ₂₉ H ₂₃ FN ₅ O [M + H] ⁺ : 476.1881, found: 476.1896; Analysis: Calculated for C ₂₉ H ₂₂ FN ₅ O: C, 73.25; H, 4.66; N, 14.73. Found: C, 73.2; H, 4.63; N, 14.4.

5 - ((3-Fluoro-4-hydroxybenzyl) (4H-1,2,4-triazol-4-yl) amino) biphenyl-2-carbonitrile (САВ06043)

To a solution of the CAV06041 compound (0.798 g, 1.678 mmol) in THF (20 ml) and methanol (20 ml) was added Pd-C (0.10 g, 5% Pd). The mixture was stirred in an H2 atmosphere for 48 hours, then the catalyst was filtered off (through celite) and the volatiles were removed under reduced pressure. The residue was recrystallized from EtOAc to give colorless fine crystals. t _square > 210 ° C (with decomposition); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.00 (s, 2H), 6.71 (dd, J = 8.6, 2.7 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.83-6.91 (m, 2H), 7.11 (dd, J = 12.5, 2.0 Hz, 1H), 7.46-7.55 (m 5H), 7.86 (d, J = 8.6 Hz, 1H), 8.78 (s, 2H), 9.94 (s, 1H); MCHR (ER +): m / z 386.4 (100%, [M + H] ⁺ ); HRMS (ER +): calculated for C ₂₂ H ₁₆ FN ₅ ONa [M + Na] ⁺ : 402.1231, found: 402.1211.

4 - (((6-Cyanobiphenyl-3-yl) (4H-1,2,4-triazol-4-yl) amino) methyl) -2-fluorophenyl sulfamate (САВ06044)

To a solution of sulfamoyl chloride (0.399 g, 3.45 mmol) in DMA (1 ml) was added a solution of compound САВ06043 (0.161 g, 0.418 mmol) in DMA (5 ml) at 0 ° C. The clear solution was stirred at 0 ° C for 2 hours and then at room temperature for 4 hours. EtOAc (50 ml) and water (20 ml) were added, the organic layer was separated, washed with water (2 × 30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO ₂ , CHCl ₃ / acetone (1: 1)] to give CAB06044 (0.126 g, 65%) as a white solid. t _square = 198-200 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.20 (s, 2H), 6.65 (d, J = 8.6 Hz, 1H), 6.75 (s, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.30-7.58 (m, 7H), 7.86 (dd, J = 8.6 Hz, 2.3 Hz, 1H), 8.29 (s, 2H); 8.92 (s, 2H); MCHR (ER +): m / z 465.2 (100%, [M + H] ⁺ ); HRMS (ER +): calculated for C ₂₂ H ₁₈ FN ₆ O ₃ S [M + H] ⁺ : 465.1140, found: 465.1118.

2-Chloro-4-hydroxymethylphenol (САВ06028)

To a solution of 3-chloro-4-hydroxybenzaldehyde (4.697 g, 30.0 mmol) and trimethoxy borate (0.5 ml) in THF (20 ml) and EtOH (20 ml) was added NaBH _{4 in} small portions over 8 hours (2, 0 g, 52.87 mmol). The mixture was stirred overnight and EtOAc (100 ml) and water (50 ml) were added. The organic layer was separated and washed with 2M KHSO ₄ solution (30 ml) and brine (30 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO ₂ , CHCl ₃ / acetone (3: 1)], then recrystallized from EtOAc / hexane to give CAV06028 (3.82 g, 80%) as colorless small needles: t _{pl .} = 126-127 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.36 (d, J = 6.5 Hz, 2H), 5.11 (t, J = 6.5 Hz, 1H), 6.90 (d , J = 8.2 Hz, 1H), 7.06 (dd, J = 8.2, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 9.99 (s, 1H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 62.1, 116.3, 119.2, 126.4, 128.1, 134.5, 151.7; MCHP (ER-): m / z 156.9 (100%, [M-H] ^- ).

5 - ((3-Chloro-4-hydroxybenzyl) (4H-1,2,4-triazol-4-yl) amino) biphenyl-2-carbonitrile (САВ06047)

A solution of 2-chloro-4- (hydroxymethyl) phenol (САВ06028, 0.317 g, 2.0 mmol) in SOCl ₂ (5 ml) was stirred at room temperature for 0.5 h. Excess SOCl ₂ was removed under reduced pressure and the residue was dissolved in DMF (5 ml). Then, the compound CAB06022 (0.523 g, 2.0 mmol) and K ₂ CO ₃ (1.38 g, 10 mmol) were added and the mixture was vigorously stirred overnight. EtOAc (60 ml) and a 2M KHSO ₄ solution (30 ml) were added, the organic layer was separated, washed with water (10 ml) and brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified using flash chromatography [SiO ₂ , acetone / chloroform (1: 2)] and the compound CAB06047 (0.490 g, 61%) was obtained as a white solid: t _pl. = 226-228 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.00 (s, 2H), 6.70 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.87 (d, J = 8.6 Hz, 1H), 7.02 (dd, J = 8.6, 2.4 Hz, 1H), 7.46-7, 56 (m, 5H), 7.29 (d, J = 2.7 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 8.78 (s, 2H), 10, 28 (s, 1H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 56.1,101.9, 112.7, 114.1, 116.6, 118.7, 119.6, 126.1, 128.5, 128 6, 128.8, 128.9, 130.4, 135.5, 137.8, 143.4, 146.3, 151.4, 152.9; MCHR (ER +): m / z 402.3 (100%, [M + H] ⁺ ; HRMS (ER +): calculated for C ₂₂ H ₁₇ ClN ₅ P [M + H] ⁺ : 402.1116, found : 402.1105.

2-Chloro-4 - (((6-cyanobiphenyl-3-yl) (4H-1,2,4-triazol-4-yl) amino) methyl) phenyl sulfamate (САВ06049)

To a solution of sulfamoyl chloride (0.399 g, 3.45 mmol) in DMA (1 ml) at 0 ° C was added a solution of compound САВ06047 (0.20 g, 0.498 mmol) in DMA (5 ml). The clear solution was stirred at 0 ° C for 2 hours and then at room temperature for 4 hours. EtOAc (50 ml) and water (20 ml) were added, the organic layer was separated, washed with water (2 × 30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO ₂ , CHCl ₃ / acetone (2: 1)] to give CAB06045 (0.158 g, 66%) as a white solid. t _square = 201-204 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.16 (s, 2H), 6.66 (dd, J = 8.6, 2.4 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 7.38 (dd, J = 8.6, 2.3 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.46-7, 53 (m, 5H), 7.59 (d, J = 2.3 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 8.29 (s, 2H), 8, 89 (s, 2H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 56.2, 102.2, 112.6, 114.0, 118.7, 123.7, 126.5, 128.1, 128.6 , 128.8, 129.0, 130.3, 134.9, 135.6, 137.7, 143.4, 145.8, 146.3, 151.2; MCHR (ER +): m / z 481.2 (100%, [M + H] +); HRMS (ER +): calculated for C ₂₂ H ₁₈ ClN ₆ O ₃ S [M + H] ⁺ : 481.0844, found: 481.0830.

5 - ((3-Bromo-4-hydroxybenzyl) (4H-1,2,4-triazol-4-yl) amino) biphenyl-2-carbonitrile (САВ06026)

A solution of 2-bromo-4- (hydroxymethyl) phenol (0.305 g, 1.5 mmol) in SOCl ₂ (5 ml) was stirred at room temperature for 0.5 h. Excess SOCl ₂ was removed under reduced pressure and the residue was dissolved in DMF (5 ml). Then, the compound CAB06022 (0.392 g, 1.5 mmol) and K ₂ CO ₃ (1.38 g, 10 mmol) were added and the mixture was vigorously stirred overnight. EtOAc (60 ml) and a 2M KHSO ₄ solution (30 ml) were added, the organic layer was separated, washed with water (10 ml) and brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified using flash chromatography [SiO ₂ , acetone / chloroform (1: 2)] and received the connection CAV06026 (0.288 g, 43%) as a white solid: t _pl. = 218-220 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.00 (s, 2H), 6.70 (dd, J = 8.6, 2.4 Hz, 1H), 6.82 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 7.07 (dd, J = 8.2, 2.0 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.48-7.58 (m, 5H), 7.86 (d, J = 8.2 Hz, 1H), 8.79 (s, 2H), 10, 38 (s, 1H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 56.0, 101.9, 109.2, 112.7, 114.2, 116.3, 118.8, 126.5, 128.6 , 128.8, 129.0, 129.3, 133.4, 135.6, 137.8, 143.5, 146.3, 151.4, 154.0; MCHR (ER +): m / z 446.2 (100%, [M + H] ⁺ ; HRMS (ER +): calculated for C ₂₂ H ₁₇ BrN ₅ O [M + H] ⁺ : 446.0624, found : 446.0617.

2-Bromo-4 - (((6-cyanobiphenyl-3-yl) (4H-1,2,4-triazol-4-yl) amino) methyl) phenyl sulfamate (САВ06045)

To a solution of sulfamoyl chloride (0.399 g, 3.45 mmol) in DMA (1 ml) at 0 ° C was added a solution of compound САВ06026 (0.103 g, 0.231 mmol) in DMA (5 ml). The clear solution was stirred at 0 ° C for 2 hours and then at room temperature for 4 hours. EtOAc (50 ml) and water (20 ml) were added, the organic layer was separated, washed with water (2 × 30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO ₂ , CHCl ₃ / acetone (1: 1)] to give CAB06045 (0.073 g, 60%) as a white solid. t _square > 200 ° C (with decomposition); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.18 (s, 2H), 6.67 (dd, J = 8.6, 2.4 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 7.40-7.56 (m, 7H), 7.74 (d, J - 1.6 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 8.31 (s, 2H); 8.91 (s, 2H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 56.1, 102.1, 112.6, 114.0, 115.8, 118.7, 123.2, 128.5, 128.8 , 129.0, 133.4, 135.0, 135.6, 137.7, 143.4, 146.3, 147.1, 151.2; MCHR (ER +): m / z 527.2 (100%, [C ₂₂ H ₁₈ ⁸¹ BrN ₆ O ₃ S]), 525.2 (90%, C ₂₂ H ₁₈ ⁷⁹ BrN ₆ O ₃ S] ⁺ ) ; HRMS (ER +): calculated for C ₂₂ H ₁₈ ⁷⁹ BrN ₆ O ₃ S [M + H] ⁺ : 525.0339, found: 525.0320.

5-Fluoro-4'-methoxybiphenyl-2-carbonitrile (САВ06042)

A mixture of 2-bromo-4-fluorobenzonitrile (5.0 g, 25.0 mmol), 4-methoxyphenylboronic acid (4.56 g, 30 mmol), dimethoxyethane (25 ml) and 2M Na ₂ CO ₃ solution (40 ml) refluxed, then Pd ₂ (dba) ₃ (0.10 g) was added and heating was continued for 5 hours. After cooling to room temperature, CHCl ₃ (50 ml) was added to dissolve the product that crystallized from the organic layer. The mixture was filtered through celite, the organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO ₂ , CHCl ₃ ], then recrystallized from EtOH to give CAB06042 as a white solid (4.03 g, 71%). t _square = 145-147 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.87 (s, 3H), 7.02 (AA'BB ', 2H), 7.07-7.13 (m, 1H), 7.19 (dd , J = 9.4, 2.7 Hz, 1H), 7.51 (AA'BB ', 2H), 7.75 (dd, J = 8.6, 5.5 Hz, 1H); MCHR (ER +): m / z 228.2 (100%, [M + H] ⁺ ); HRMS (ER +): calculated for C ₁₄ H ₁₁ FNO [M + H] ⁺ : 228.0819, found: 228.0816; Analysis: Calculated for C ₁₄ H ₁₀ FNO: C, 74.00; H, 4.44; N, 6.16. Found: C, 73.7; H, 4.40; N, 6.09.

5- (4H-1,2,4-Triazol-4-ylamino) -4'-methoxybiphenyl-2-carbonitrile (САВ06046)

To a solution of 4H-1,2,4-triazole-4-amine (3.41 g, 40.928 mmol) in DMSO (40 ml) was added KOtBu (4.593 g, 40.928 mmol). The mixture was stirred at room temperature for 0.5 h, then the compound САВ06042 (4.65 g, 20.468 mmol) was added and stirring was continued for 1 h. The mixture was poured onto crushed ice and neutralized with a 2M KHSO ₄ solution. The precipitate was filtered off and recrystallized from acetone / Et ₂ O to give CAB06046 (5.07 g, 85%) as a light yellow crystalline solid, _mp. = 176-177 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.81 (s, 3H), 6.47 (d, J = 2.4 Hz, 1H), 6.54 (dd, J = 8.6, 2.4 Hz, 1H), 7.07 (AA'BB ', 2H), 7.43 (AA'BB', 2H), 7.77 (J = 8.6 Hz, 1H), 8.86 ( s, 2H); 10.28 (s, 1H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 55.3, 101.2, 111.0, 112.3, 114.2, 119.1, 129.7, 130.0, 135.6 , 144.1, 146.1, 150.8, 159.8; MCHR (ER +): m / z 292.3 (100%, [M + Hf); MCBP (ER +): calculated for C ₁₆ H ₁₄ N ₅ O [M + H] ⁺ : 292.1193, found: 292.11180; Analysis: Calculated for C ₁₆ H ₁₃ N ₅ O: C, 65.97; H, 4.50; N, 24.04. Found: C, 65.9; H, 4.56; N, 23.8.

5 - ((4- (Benzyloxy) benzyl) (4H-1,2,4-triazol-4-yl) amino) -4'-methoxybiphenyl-2-carbonitrile (САВ06065)

To a solution of the CAV06046 compound (0.874 g, 3.0 mmol) in DMF (20 ml) was added NaH (0.120 g, 3.0 mmol, 60% in mineral oil) at room temperature. The mixture was stirred for 0.5 h, then benzyloxybenzyl chloride (0.698 g, 3.0 mmol) was added and stirring was continued for 18 h. The reaction mixture was diluted with EtOAc (50 ml), washed with water (3 × 30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was recrystallized from 2-propanol to give CAB06065 (1.112 g, 76%) as colorless needles. t _square = 219-221 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.81 (s, 3H), 5.04 (s, 2H), 5.06 (s, 2H), 6.69 (dd, J = 8, 6, 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.95 (AA'BB ', 2H), 7.07 (AA'BB', 2H), 7.23 (AA'BB ', 2H), 7.30-7.44 (m, 5H), 7.47 (AA'BB', 2H), 7.82 (d, J = 8.6 Hz, 1H), 8.77 (s, 2H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 55.3, 56.5, 69.2, 101.7, 112.3, 113.8, 114.2, 114.8, 119.0 , 126.6, 127.8, 127.9, 128.4, 129.9, 130.0, 130.1, 135.5, 136.9, 143.4, 146.0, 151.5, 158 , 2, 159.9; MCHP (ER +): m / z 488.2 (100%, [M + H] ⁺ ); MCBP (ER +): calculated for C ₃₀ H ₂₆ N ₅ O ₂ [M + H] ⁺ : 476.1881, found: 488.2063; Analysis: Calculated for C ₃₀ H ₂₅ N ₅ O ₂ : C, 73.90; H, 5.17; N, 14.36. Found: C, 73.7; H, 5.10; N, 14.3.

5 - ((4-Hydroxybenzyl) (4H-1,2,4-triazol-4-yl) amino) -4'-methoxybiphenyl-2-carbonitrile (САВ06073)

To a solution of compound CAB06065 (0.95 g, 1.95 mmol) in THF (20 ml) and methanol (20 ml) was added Pd-C (0.10 g, 5% Pd). The mixture was stirred in an H ₂ atmosphere for 48 h, then the catalyst was filtered off (through celite) and the volatiles were removed under reduced pressure. The residue was recrystallized from EtOH to give CAB06073 (0.69 g, 89%) as colorless crystals. t _square = xxx-xxx ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.81 (s, 3H), 4.96 (s, 2H), 6.65-6.71 (m, 3H), 6.74 (d, J = 8.6 Hz, 1H), 7.04-7.10 (m, 4H), 7.46 (AA'BB ', 2H), 7.81 (d, J = 8.6 Hz, 1H) 8.71 (s, 2H); 9.49 (s, 1H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 55.3, 56.6, 101.6, 112.3, 113.8, 114.2, 115.4, 119.0, 124.5 , 129.9, 130.0, 130.2, 135.5, 143.5, 146.0, 151.5, 157.2, 159.9; MCHR (ER +): m / z 398.2 (100%, [M + H] ⁺ ); MCBP (ER +): calculated for C ₂₃ H ₁₉ N ₅ O ₂ Na [M + Na] ⁺ : 420.1431, found: 420.1410; Analysis: Calculated for C ₂₃ H ₁₉ N ₅ O ₂ : C, 69.51; H, 4.82; N, 17.62. Found: C, 69.3; H, 4.80; N, 17.65.

4 - (((6-Cyano-4'-methoxybiphenyl-3-yl) (4H-1,2,4-triazol-4-yl) amino) methyl) phenyl sulfamate (САВ06077)

To a solution of sulfamoyl chloride (0.399 g, 3.45 mmol) in DMA (1 ml) at 0 ° C was added a solution of compound САВ06073 (0.200 g, 0.503 mmol) in DMA (5 ml). The clear solution was stirred at 0 ° C for 2 hours and then at room temperature for 4 hours. EtOAc (50 ml) and water (20 ml) were added, the organic layer was separated, washed with water (2 × 30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was recrystallized from EtOAc to give CAB06077 (0.194 g, 81%) as a white solid. t _square = 184-186 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.81 (s, 3H), 6.65 (dd, J = 8.6, 2.3 Hz. 1H), 6.71 (d, J = 2.3 Hz, 1H), 7.07 (AA'BB ', 2H), 7.24 (AA'BB', 2H), 7.43 (AA'BB ', 2H), 7.45 (AA' BB ', 2H), 7.83 (d, J = 8.6 Hz, 1H), 8.03 (s, 2H), 8.85 (s, 2H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 55.3, 56.6, 101.8, 112.2, 113.7, 114.2, 118.9, 122.2, 129.7 , 129.9, 130.0, 133.3, 135.5, 143.4, 146.0, 149.8, 151.3, 159.9; MCHR (ER +): m / z 477.3 (100%, [M + H] ⁺ ); MCBP (ER +): calculated for C ₂₃ H ₂₁ N ₆ O ₄ S [M + H] ⁺ : 477.1340, found: 477.1328.

5,4'-Difluorobiphenyl-2-carbonitrile (САВ06058)

A mixture of 2-bromo-4-fluorobenzonitrile (5.0 g, 25.0 mmol), 4-fluorophenylboronic acid (3.85 g, 27.5 mmol), dimethoxyethane (30 ml) and 2M Na ₂ CO ₃ solution (40 ml) was refluxed, then Pd ₂ (dba) ₃ (0.10 g) was added and heating was continued for 5 hours. After cooling to room temperature, CHCl3 (50 ml) was added and the mixture was filtered (through celite). The organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO ₂ , CHCl ₃ ], then recrystallized from CHCl ₃ / n-hexane to give CAB06058 (4.03 g, 71%) as colorless needles. t _square = 111-113 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.12-7.23 (m, 4H), 7.50-7.56 (m, 2H), 7.76 (dd, J = 8.6, 5 4 Hz, 1H); MCHP (ER +): m / z 416.0 (100%, [M + H] ⁺ ); MCBP (ER +): calculated for C ₁₃ H ₈ F ₂ N [M + H] ⁺ : 216.0619, found: 216.0613; Analysis: Calculated for C ₁₃ H ₇ F ₂ N: C, 72.56; H, 3.28; N, 6.51. Found: C, 72.4; H, 3.28; N, 6.55.

5- (4H-1,2,4-Triazol-4-ylamino) -4'-fluorobiphenyl-2-carbonitrile (САВ06062)

To a solution of 4H-1,2,4-triazole-4-amine (1.711 g, 20.35 mmol) in DMSO (30 ml) was added KOtBu (2.28 g, 20.35 mmol). The mixture was stirred at room temperature for 0.5 h, then the compound САВ06058 (2.19 g, 10.17 mmol) was added and stirring was continued for 1 h. The mixture was poured onto crushed ice and neutralized with a 2M KHSO ₄ solution. The precipitate was filtered off, washed with water, and recrystallized from EtOAc / n-hexane to give CAB06062 (2.07 g, 73%) as a light yellow crystalline solid. t _square = 231-234 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.50 (d, J = 2.4 Hz, 1H), 6.58 (dd, J = 8.6, 2.4 Hz, 1H), 7 32-7.38 (m, 2H), 7.51-7.58 (m, 2H), 7.80 (d, J = 8.6 Hz, 1H), 8.86 (s, 2H), 10.32 (s, 1H); MCHR (ER +): m / z 280.1 (100%, [M + H] ⁺ ); HRMS (ER +): calculated for C ₁₅ H ₁₀ FN ₅ [M + H] ⁺ : 280.0993, found: 280.0982; Analysis: Calculated for C ₁₅ H ₁₀ FN ₅ : C, 64.51; H, 3.61; N, 25.08. Found: C, 64.4; H, 3.57; N, 24.8.

5 - ((4- (Benzyloxy) benzyl) (4H-1,2,4-triazol-4-yl) amino) -4'-fluorobiphenyl-2-carbonitrile (САВ06064)

To a solution of the CAV06062 compound (0.838 g, 3.0 mmol) in DMF (20 ml) was added NaH (0.120 g, 3.0 mmol, 60% in mineral oil) at room temperature. The mixture was stirred for 0.5 h, then benzyloxybenzyl chloride (0.698 g, 3.0 mmol) was added and stirring was continued for 18 h. The reaction mixture was diluted with EtOAc (50 ml), washed with water (3 × 30 ml) and brine (30 ml), dried (Kaz804) and concentrated under reduced pressure. The residue was recrystallized from 2-propanol to give CAB06064 (1.127 g, 79%) as colorless crystals. t _square = 211-213 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.05 (s, 2H), 5.06 (s, 2H), 6.70 (dd, J = 8.6 Hz, 2.3 Hz, 1H ), 6.83 (d, J = 2.3 Hz, 1H), 6.88 (AA'BB ', 2H), 7.21 (AA'BB', 2H), 7.30-7.44 ( m, 7H), 7.55-7.60 (m, 2H), 7.85 (d, J = 8.6 Hz, 1H), 8.75 (s, 2H); MCHR (ER +): m / z 476.3 (100%, [M + H] ⁺ ); HRMS (ER +): calculated for C ₂₉ H ₂₃ FN ₅ O [M + H] ⁺ : 476.1881, found: 476.1860; Analysis: Calculated for C ₂₉ H ₂₂ FN ₅ O: C, 73.25; H, 4.66; N, 14.73. Found: C, 73.3; H, 4.64; N, 14.8.

4'-Fluoro-5 - ((4-hydroxybenzyl) (4H-1,2,4-triazol-4-yl) amino) biphenyl-2-carbonitrile (САВ06069)

To a solution of compound CAB06064 (0.93 g, 1.96 mmol) in THF (20 ml) and methanol (20 ml) was added Pd-C (0.10 g, 5% Pd). The mixture was stirred under H ₂ for 48 h, then the catalyst was filtered off (through celite) and the volatiles were removed under reduced pressure. The residue was recrystallized from EtOH to give CAB06069 (0.68 g, 90%) as light yellow crystals. t _square = 205-208 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.97 (s, 2H), 6.67 (AA'BB ', 2H), 6.70 (dd, J = 8.6, 2.4 Hz , 1H), 6.82 (d, J = 2.4 Hz, 1H), 7.06 (AA'BB ', 2H), 7.34-7.40 (m, 2H), 7.55-7 60 (m, 2H), 7.84 (d, J = 8.6 Hz, 1H), 8.71 (s, 2H), 9.49 (s, 1H); MCHR (ER +): m / z 386.1 (100%, [M + H] ⁺ ); MCBP (ER +): calculated for C ₂₂ H ₁₇ FN ₅ O [M + H] ⁺ : 386.1412, found: 386.1397; Analysis: Calculated for C ₂₂ H ₁₆ FN ₅ O: C, 68.56; H, 4.18; N, 18.17. Found: C, 68.6; H, 4.18; N, 18.3.

4 - (((6-Cyano-4'-fluorobiphenyl-3-yl) (4H-1,2,4-triazol-4-yl) amino) methyl) phenyl sulfamate (САВ06078)

To a solution of sulfamoyl chloride (0.399 g, 3.45 mmol) in DMA (1 ml) at 0 ° C was added a solution of compound САВ06069 (0.207 g, 0.503 mmol) in DMA (5 ml). The clear solution was stirred at 0 ° C for 2 hours and then at room temperature for 4 hours. EtOAc (50 ml) and water (20 ml) were added, the organic layer was separated, washed with water (2 × 30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was recrystallized from EtOAc to give CAB06078 (0.197 g, 79%) as a white solid. t _square = 197-199 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.17 (s, 2H), 6.67 (dd, J = 8.6, 2.4 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 7.23 (AA'BB ', 2H), 7.31-7.44 (m, 4H), 7.52-7.60 (m, 2H), 7.86 ( d, J = 8.6 Hz, 1H), 8.03 (s, 2H), 8.84 (s, 2H); LRMS (ES +): m / z 465,4 ^{(100%, [M + H] +} ); MCBP (ER +): calculated for C ₂₂ H ₁₈ FN ₆ O ₃ S [M + H] ⁺ : 477.1140, found: 465.1123.

5 - ((4- (Benzyloxy) benzyl) (4H-1,2,4-triazol-4-yl) amino) biphenyl-2,4'-dicarbonitrile (САВ06075)

A mixture of 4 - ((4- (benzyloxy) benzyl) (4H-1,2,4-triazol-4-yl) amino) -2-bromobenzonitrile (САВ05114, 0.460 g, 1.0 mmol), 4-cyanophenylboronic acid ( 0.184 g, 1.25 mmol), dimethoxyethane (20 ml) and 2M Na ₂ CO ₃ solution (20 ml) were refluxed, then Pd ₂ (dba) ₃ (0.05 g) was added and heating was continued for 5 h. After cooling to room temperature, EtOAc (50 ml) was added and the mixture was filtered (through celite). The organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified using flash chromatography [SiO ₂ , CHCl ₃ / acetone (2: 1)] and the compound CAV06075 (4.03 g, 71%) was obtained as a white solid. t _square = 234-237-113 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.02 (s, 4H), 6.72 (dd, J = 8.6, 2.7 Hz, 1H), 6.91 (d, J = 2.7 Hz, 1H), 6.95 (AA'BB ', 2H), 7.21 (AA'BB', 2H), 7.30-7.45 (m, 5H), 7.75 (AA 'BB', 2H), 7.90 (d, J = 8.6 Hz, 1H), 8.02 (AA'BB ', 2H), 8.75 (s, 2H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 56.5, 69.2, 101.7, 111.7, 113.4, 113.7, 114.1, 114.8, 118.3 , 118.4, 126.4, 127.8, 127.9, 128.4, 129.7, 130.0, 130.1, 132.7, 135.6, 136.9, 142.3, 143 3, 144.5, 145.9, 151.5, 158.2; MCHR (ER +): m / z 483.3 (100%, [M + H] ⁺ ; HRMS (ER +): calculated for C ₃₀ H ₂₃ N ₆ O [M + H] ⁺ : 483.1928, found : 483.1918.

5 - ((4-Hydroxybenzyl) (4H-1,2,4-triazol-4-yl) amino) biphenyl-2,4'-dicarbonitrile (САВ06076)

To a solution of the CAV06075 compound (0.21 g, 0.417 mmol) in THF (20 ml) and methanol (20 ml) was added Pd-C (0.05 g, 5% Pd). The mixture was stirred under H ₂ for 48 h, then the catalyst was filtered off (through celite) and the volatiles were removed under reduced pressure. The residue was suspended in EtOAc and refluxed for 5 minutes. After cooling to room temperature, the precipitate was filtered off and dried under high vacuum, and CAB06076 (0.146 g, 89%) was obtained as a white solid. t _square = 221-223 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.98 (s, 2H), 6.67 (AA'BB ', 2H), 6.73 (dd, J = 8.6, 2.4 Hz , 1H), 6.91 (d, J = 2.4 Hz, 1H), 7.06 (AA'BB ', 2H), 7.75 (AA'BB', 2H), 7.89 (d, J = 8.6 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 8.70 (s, 2H), 9.51 (s, 1H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 56.5, 101.6, 111.7, 113.4, 114.1, 115.4, 118.4, 118.5, 124.3 , 129.7, 130.2, 132.7, 135.6, 142.3, 143.4, 144.5, 151.6, 157.3; MCHR (ER +): m / z 393.1 (100%, [M + H] ⁺ ); HRMS (ER +): calculated for C ₂₃ H ₁₇ N ₆ O [M + H] ⁺ : 393.1458, found: 393.1450.

4 - (((4 ', 6-Dicyanobiphenyl-3-yl) (4H-1,2,4-triazol-4-yl) amino) methyl) phenyl sulfamate (САВ06088)

To a solution of sulfamoyl chloride (0.399 g, 3.45 mmol) in DMA (1 ml) at 0 ° C was added a solution of compound САВ06076 (0.102 g, 0.26 mmol) in DMA (5 ml). The clear solution was stirred at 0 ° C for 2 hours and then at room temperature for 4 hours. EtOAc (50 ml) and water (20 ml) were added, the organic layer was separated, washed with water (2 × 30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified using flash chromatography [8C, CHCl ₃ / acetone (1: 1)] to give the compound CAB06088 (0.065 g, 53%) as a white solid, _mp. > 140 ° C (with decomposition); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.17 (s, 2H), 6.60 (dd, J = 8.6, 2.4 Hz, 2H), 6.87 (d, J = 2.4 Hz, 2H), 7.22 (AA'BB ', 2H), 7.40 (AA'BB', 2H), 7.71 (AA'BB ', 2H), 7.89 (d, J = 8.6 Hz, 1H), 7.99 (AA'BB ', 2H), 8.02 (s, 2H), 8.83 (s, 2H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 56.5, 101.9, 111.8, 113.3, 114.0, 118.3, 118.5, 122.3, 129.7 , 129.8, 132.7, 133.1, 135.7, 142.2, 143.4, 144.6, 149.9, 151.4; MCHR (ER +): m / z 471.2 (100%, [M + H] ⁺ ; HRMS (ER +): calculated for C ₂₃ H ₁₈ N ₇ O ₃ S [M + H] ⁺ : 472.1186 Found: 472.1180.

4 '- (Benzyloxy) -5-fluorobiphenyl-2-carbonitrile (САВ06048)

A mixture of 2-bromo-4-fluorobenzonitrile (4.50 g, 22.5 mmol), 4-benzyloxyphenylboronic acid (5.19 g, 22.76 mmol), dimethoxyethane (25 ml) and 2M Na ₂ CO ₃ solution (40 ml) was refluxed, then Pd ₂ (dba) ₃ (0.05 g, 0.055 mmol) was added and heating was continued for 5 hours. After cooling to room temperature, CHCl ₃ (about 100 ml) was added to dissolve the product, which crystallized from the organic layer. The mixture was filtered through celite, the organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was recrystallized from CHCl ₃ / hexane to give CAB06048 (5.32 g, 78%) as colorless needles. t _square = 94-96 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.12 (s, 2H), 7.06-7.12 (m, 3H), 7.18 (dd, J = 9.4, 2.7 Hz, 1H), 7.33-7.53 (m, 7H), 7.74 (dd, J = 8.6, 5.7 Hz, 1H); MCHR (ER +): m / z 326.4 (100%, [M + Na] ⁺ ), 304.3 (60%, [M + H] ⁺ ); MCBP (ER +): calculated for C ₂₀ H ₁₅ FNO [M + H] ⁺ : 304.1132, found: 304.1125.

5- (4H-1,2,4-Triazol-4-ylamino) -4 '- (benzyloxy) biphenyl-2-carbonitrile (САВ06050)

To a solution of 4H-1,2,4-triazole-4-amine (2.439 g, 29.01 mmol) in DMSO (50 ml) was added KOtBu (3.36 g, 30.0 mmol). The mixture was stirred at room temperature for 0.5 h, then the compound САВ06048 (4.40 g, 14.51 mmol) was added and stirring was continued for 1 h. The mixture was poured onto crushed ice and neutralized with a 2M KHSO ₄ solution. The precipitate was filtered off and recrystallized from EtOAc / n-hexane to give CAV06050 (5.07 g, 85%) as colorless fine needles. t _square = 180-182 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.17 (s, 2H), 6.47 (d, J = 2.4 Hz, 1H), 6.54 (dd, J = 8.6, 2.4 Hz, 1H), 7.15 (AA'BB ', 2H), 7.32-7.50 (m, 7H), 7.78 (d, J = 8.6 Hz, 1H), 8 86 (s, 2H); 10.28 (s, 1H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 69.4, 101.2, 111.0, 112.3, 115.0, 119.1, 127.8, 127.9, 128.5 , 129.7, 130.2. 135.6, 136.8, 144.1, 146.0, 150.8, 158.9; MCHR (ER +): m / z 368.2 (100%, [M + H] ⁺ ); HRMS (ER +): calculated for C ₂₂ H ₁₈ N ₅ O [M + H] ⁺ : 368.1506, found: 368.1494.

4 '- (Benzyloxy) -5 - ((4-bromobenzyl) (4H-1,2,4-triazol-4-yl) amino) biphenyl-2-carbonitrile (САВ06051)

To a solution of the CAV06050 compound (2.20 g, 5.99 mmodia) in DMF (20 ml), NaH (0.240 g, 6.0 mmol) was added at room temperature. The mixture was stirred for 0.5 h until hydrogen evolution ceased, then 4-bromobenzyl bromide (1.497 g, 5.99 mmol) was added and stirring was continued for 18 hours. The reaction mixture was diluted with EtOAc (60 ml), washed with water (3 × 30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was recrystallized from EtOH to give CAB06051 (2.65 g, 82%) as light yellow fine needles. t _square = 186-188 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.12 (s, 2H), 5.18 (s, 2H), 6.64 (dd, J = 8.6, 2.4 Hz, 1H), 6 75 (d, J = 2.4 Hz, 1H), 7.14 (AA'BB ', 2H), 7.28 (AA'BB', 2H), 7.30-7.50 (m, 5H ), 7.53 (AA'BB ', 2H), 7.82 (AA'BB', 2H), 8.79 (s, 2H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 56.5, 69.3, 101.9, 112.3, 113.8.115.0, 118.9, 121.3, 127.7, 127 , 9, 128.5, 129.9, 130.1, 130.7, 131.6, 134.2, 135.5, 136.8, 149.4, 146.0, 151.3, 159.0 ; MCHR (ER +): m / z 536.2 (100%, [M + H] ⁺ ); MCBP (ER +): calculated for C ₂₉ H ₂₃ BrN ₅ O [M + H] ⁺ : 536.1080, found: 536.1064.

5- (Benzyl- [1,2,4] triazol-4-ylamino) -4'-hydroxybiphenyl-2-carbonitrile (САВ06052)

To a solution of the CAV06051 compound (0.536 g, 1.00 mmol) in THF (20 ml) and methanol (20 ml) was added Pd-C (0.050 g, 5% Pd). The mixture was stirred under H ₂ for 48 h, then the catalyst was filtered off (through celite) and the volatiles were removed under reduced pressure. The residue was purified by flash chromatography [SiO ₂ , CHCl ₃ / acetone (3: 1) to give CAB06052 (0.297 g, 81%) as a white solid. t _square = 229-230 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.12 (s, 2H), 6.65 (dd, J = 8.6, 2.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.88 (AA'BB ', 2H), 5.28-7.36 (m, 7H), 7.80 (d, J = 8.6 Hz, 1H), 8 81 (s, 2H); 9.82 (s, 1H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 57.2, 101.7, 112.0, 113.6, 115.5, 119.1, 128.0, 128.4, 128.5 , 128.7, 129.8, 134.8, 135.8, 143.4, 146.4, 151.5, 158.3; MCHR (ER +): m / z 368.4 (100%, [M + H] ⁺ ); HRMS (ER +): calculated for C ₂₂ H ₂₈ N ₅ O [M + H] ⁺ : 368.1506, found: 368.1490.

5 '- (Benzyl (4H-1,2,4-triazol-4-yl) amino) -2'-cyanobiphenyl-4-yl sulfamate (САВ06054)

To a solution of sulfamoyl chloride (0.399 g, 3.45 mmol) in DMA (1 ml) at 0 ° C was added a solution of compound САВ06052 (0.152 g, 0.414 mmol) in DMA (5 ml). The clear solution was stirred at 0 ° C for 2 hours and then at room temperature for 4 hours. EtOAc (50 ml) and water (20 ml) were added, the organic layer was separated, washed with water (2 × 30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was recrystallized from acetone / hexane to give CAB06054 (0.127 g, 69%) as a white solid. t _square = 157-160 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.15 (s, 2H), 6.72-6.78 (m, 2H), 7.26-7.35 (m, 5H), 7, 42 (AA'BB ', 2H), 7.61 (AA'BB', 2H), 7.88 (d, J = 8.6 Hz, 1H), 8.13 (s, 2H), 8.81 (s, 2H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 57.2, 101.8, 112.7, 113.9, 118.7, 122.5, 128.1, 128.5, 128.7 , 130.1, 134.7, 135.6, 136.0, 143.4, 145.2, 150.6, 151.5; MCHR (ER +): m / z 447.3 (100%, [M + H] ⁺ ; HRMS (ER +): calculated for C ₂₂ H ₁₉ N ₆ O ₃ S [M + H] ⁺ : 447.1234 Found: 447.1221.

5 - ((4-Bromobenzyl) (4H-1,2,4-triazol-4-yl) amino) -4'-hydroxybiphenyl-2-carbonitrile (САВ06056)

A solution of compound САВ06051 (0.536 g, 1.00 mmol) in AcOH (4 ml) and concentrated HCl (2 ml) was heated at 100 ° C for 1 h. After cooling to room temperature, EtOAc (50 ml) was added and the mixture was washed with water (2 (30 ml) and concentrated NaHCO ₃ solution (30 mL). The organic layer was dried (Na ₂ SO ₄₎ and concentrated under reduced pressure. The residue was recrystallized from a mixture of EtOAc / petroleum ether (40-60 ° C) to give compound SAV06056 (0.433 g, 97%) as a white solid, mp = 222-224 ° C; ₁ H NMR (400 MHz, DMSO-d ₆ ) δ 5.11 (s, 2H), 6.63 (dd, J = 8.6, 2.7 Hz, 2H), 6.70 (d, J = 2.7 Hz, 1H) 6.87 (AA'BB ', 2H), 7.27 (AA'BB ', 2H), 7.33 (AA'BB', 2H), 7.52 (AA'BB ', 2H), 8.82, (s, 2H), 9.82 (s, 1H ); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 56.5, 101.8, 112.1, 113.6.115.5.119.0, 121.3, 128.3, 129.9, 130 7, 131.6, 134.3, 135.5, 143.4, 146.4, 151.3, 158.3; MCHR (ER +): m / z 446.0 (100%, [C ₂₂ H ₁₇ ⁸¹ BrN ₅ O] ⁺ ), 444.0 (95%, [C ₂₂ H ₁₇ ⁷⁹ BrN ₅ O] ⁺ ); HRMS (ER +): calculated for C ₂₂ H ₁₇ ⁸¹ BrN ₅ O [M + H ] ⁺ : 446.0611, found: 446.0596.

5 '- ((4-Bromobenzyl) (4H-1,2,4-triazol-4-yl) amino) -2'-cyanobiphenyl-4-yl sulfamate (САВ06059)

To a solution of sulfamoyl chloride (0.399 g, 3.45 mmol) in DMA (1 ml) at 0 ° C was added a solution of compound САВ06056 (0.223 g, 0.50 mmol) in DMA (5 ml). The clear solution was stirred at 0 ° C for 2 hours and then at room temperature for 4 hours. EtOAc (50 ml) and water (20 ml) were added, the organic layer was separated, washed with water (2 × 30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO ₂ , CHCl ₃ / acetone (2: 1)] to give CAB06059 (0.199 g, 76%) as a white solid. t _square = 122-123 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.13 (s, 2H), 6.72-6.77 (m, 2H), 7.29 (AA'BB ', 2H), 7.42 (AA'BB ', 2H), 7.53 (AA'BB', 2H), 7.61 (AA'BB ', 2H), 7.88 (d, J = 8.6 Hz, 1H), 8 13 (s, 2H); 8.83 (s, 2H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 56.5, 102.0, 112.8, 114.0, 118.6, 121.4, 122.5, 130.1, 130.7 , 131.6, 134.2, 135.7, 135.9, 143.4, 145.2, 150.6, 151.4; MCHR (ER +): m / z 525.1 (100%, [C ₂₂ H ₁₈ ⁷⁹ BrN ₆ O ₃ S] ⁺ ), 527.1 (80%, [C ₂₂ H ₁₈ ⁸¹ BrN ₆ O ₃ S] ⁺ ); MCBP (ER +): calculated for C ₂₂ H ₁₈ ⁷⁹ BrN ₆ O ₃ S [M + H] ⁺ : 525.0339, found: 525.0318.

(E / Z) -N- (4- (Benzyloxy) benzylidene) -1H-1,2,4-triazole-1-amine (САВ06086)

To a solution of 1,2,4-triazole (1.38 g, 20.0 mmol) and NaOH (1.60 g, 40.0 mmol) in water, hydroxylamine-0-sulfonic acid (2.26 g, 20.0 mmol). The pink solution was heated at 70 ° C for 1 h and then concentrated under reduced pressure. The residue was suspended in EtOH (50 ml) and the solids were filtered. 4-Benzyloxybenzaldehyde (2.12 g, 10.0 mmol) and p-TsOH · H ₂ O (0.05 g) were added to the filtrate, and the resulting mixture was refluxed for 15 minutes. The clear solution was kept at room temperature overnight. The product crystallized from the solution and was collected by filtration to obtain the CAV06086 compound (2.39 g, 86%) as colorless plates. t _square = 121-123 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.20 (s, 2H), 7.18 (AA'BB ', 2H), 7.30-7.48 (m, 5H), 7.91 (AA'BB ', 2H), 8.15 (s, 1H), 8.89 (s, 1H), 9.17 (s, 1H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 69.5, 115.4, 124.7, 127.8, 128.0, 128.5, 130.6, 136.5, 142.0 , 149.5, 153.4, 161.5; MCHR (ER +): m / z 279.1 (100%, [M + H] ⁺ ); HRMS (ER +): calculated for C ₁₆ H ₁₅ N ₄ O [M + H] ⁺ : 279.1240, found: 279.1245.

N- (4- (Benzyloxy) benzyl) -1H-1,2,4-triazole-1-amine (САВ06089)

To a solution of the CAV06086 compound (1.392 g, 5.0 mmol) in THF (20 ml) and MeOH (20 ml) at 0 ° C was added NaBH ₄ (0.20 g 5.28 mmol). The mixture was stirred at 0 ° C for 1 h and then at room temperature then for 12 h (the progress of the reaction was monitored by TLC). The mixture was poured into water (50 ml) and the products were extracted with EtOAc (3 × 40 ml). The combined organic fractions were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified using flash chromatography [SiO ₂ , acetone / CHCl ₃ (1: 1)] to give compound CAB06089 (1.163 g, 83%) as a white solid. t _square = 123-124 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.16 (d, J = 3.5 Hz, 2H), 5.06 (s, 2H), 6.93 (AA'BB ', 2H), 7.16 (AA'BB ', 2H), 7.29-7.46 (m, 6H), 7.89 (s, 1H), 8.14 (s, 1H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 54.0, 69.1, 114.5, 127.7, 127.8, 128.4, 128.9, 129.9, 137.1 , 142.7, 149.5, 157.7; MCHR (ER +): m / z 281.0 (100%, [M + H] ⁺ ); HRMS (ER +): calculated for C ₁₆ H ₁₇ N ₄ O [M + H] ⁺ : 281.1397, found: 281.1401; Analysis: Calculated for C ₁₆ H ₁₆ FN ₄ O: C, 68.55; H, 5.75; N, 19.99. Found: C, 68.2; H, 5.80; N, 20.0.

5 - ((4- (Benzyloxy) benzyl) (1H-1,2,4-triazol-1-yl) amino) biphenyl-2-carbonitrile (САВ06090)

To a solution of the CAV06089 compound (0.280 g, 1.00 mmol) in DMSO (10 ml) was added KOtBu (0.123 g, 1.10 mmol). The mixture was stirred at room temperature for 0.5 h, then the CAV06020 compound (0.197 g, 1.00 mmol) was added and stirring was continued overnight. Then water (30 ml) was added and the mixture was extracted with EtOAc (3 × 30 ml). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO ₂ , acetone / CHCl ₃ (1: 6)] to give the compound CAB06090 (0.362 g, 79%) as a colorless oil, which was crystallized from MeOH (colorless crystals). t _square = 112-113 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.02 (s, 2H), 5.06 (s, 2H), 6.68 (dd, J = 8.6, 2.3 Hz, 1H) 6.84 (d, J = 2.4 Hz, 1H), 6.95 (AA'BB ', 2H), 7.25 (AA'BB', 2H), 7.30 7.52 (m, UN), 7.84 (d, J = 8.6 Hz, 1H), 8.16 (s, 1H), 8.56 (s, 1H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 56.3, 69.2, 102.5, 113.6, 114.7, 115.0, 118.7, 126.7, 127.7 , 127.8, 128.4, 128.5, 128.7, 128.9, 130.1, 135.3, 136.9, 137.8, 145.1, 146.1, 151.1, 151 4, 158.1; MCHR (ER +): m / z 458.3 (100%, [M + H] ⁺ ); HRMS (ER +): calculated for C ₂₉ H ₂₄ N ₅ O [M + H] ⁺ : 458.1975, found: 458.1972; Analysis: Calculated for C ₂₉ H ₂₃ N ₅ O: C, 76.13; H, 5.07; N, 15.31. Found: C, 76.0; H, 5.04; N, 15.2.

5 - ((4-Hydroxybenzyl) (1H-1,2,4-triazol-1-yl) amino) biphenyl-2-carbonitrile (САВ06093)

To a solution of the CAV06090 compound (0.273 g, 0.597 mmol) in THF (10 ml) and methanol (10 ml) was added Pd-C (0.05 g, 5% Pd). The mixture was stirred in an H ₂ atmosphere for 18 hours, then the catalyst was filtered off (through celite) and the volatiles were removed under reduced pressure. The residue was recrystallized from EtOAc / n-hexane to give CAB06093 (0.210 g, 96%) as colorless crystals. t _square = 169-170 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.93 (s, 2H), 6.67 (AA'BB ', 2H), 6.69 (dd, J = 8.6, 2.3 Hz , 1H), 6.83 (d, J = 2.3 Hz, 1H), 7.10 (AA'BB ', 2H), 7.45-7.56 (m, 5H), 7.84 (d , J = 8.6 Hz, 1), 8.48 (s, 1H), 9.46 (s, 1H); ¹³ C NMR (100.6 MHz, DMSO-d ₆ ) δ 56.4, 102.4, 113.7, 115.0, 115.2, 118.8, 124.5, 128.6, 128.7 , 128.9, 130.2, 135.3, 137.8, 145.1, 146.1, 151.1, 151.4, 157.1; MCHR (ER +): m / z 368.2 (100%, [M + H] ⁺ ); HRMS (ER +): calculated for C ₂₂ H ₁₈ N ₅ O [M + H] ⁺ : 368.1506, found: 368.1495.

4 - (((6-Cyanobiphenyl-3-yl) (1H-1,2,4-triazol-1-yl) amino) methyl) phenyl sulfamate (САВ06094)

To a solution of sulfamoyl chloride (0.399 g, 3.45 mmol) in DMA (1 ml) at 0 ° C was added a solution of compound САВ06093 (0.100 g, 0.272 mmol) in DMA (5 ml). The clear solution was stirred at 0 ° C for 2 hours and then at room temperature for 4 hours. EtOAc (50 ml) and water (20 ml) were added, the organic layer was separated, washed with water (2 × 30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO _2, CHCl ₃ / acetone (1: 2)] to give compound SAV06094 (0.103 g, 85%) as a colorless foamy substance. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.92 (s, 2H), 5.30 (s, 2H), 6.65 (dd, J = 8.6, 2.3 Hz, 1H), 6 73 (d, J = 2.3 Hz, 1H), 7.20-7.34 (m, 5H), 7.40-7.48 (m, 4H), 7.66 (d, J = 8 6 Hz, 1H); 7.85 (s, 1H); 7.98 (s, 1H); ¹³ C NMR (100.6 MHz, CDCl ₃ ) δ 57.6, 105.2, 113.9, 116.0, 118.5, 122.7, 128.6, 128.8, 129.1, 130 , 1, 133.0, 135.3, 137.7, 144.1, 147.4, 150.2, 151.0, 151.5; MCHR (ER +): m / z 447.2 (80%, [M + H] ⁺ ), 378.1 (100%); MCBP (ER +): calculated for C ₂₂ H ₁₉ N ₆ O ₃ S [M + H] ⁺ : 447.1234, found: 447.1230.

2- (Benzofuran-2-yl) -4-fluorobenzonitrile (AUP01158-1)

A mixture of 2-bromo-4-fluorobenzonitrile (5.15 g, 25.65 mmol), benzofuran-2-ylboronic acid (5.0 g, 30.8 mmol), 1,2-dimethoxyethane (25 ml) and 2M solution Na ₂ CO ₃ (40 ml) was refluxed, then Pd ₂ (dba) ₃ (100 mg) was added and heating was continued for 5 hours. After cooling to RT (room temperature), EtOAc (20 ml) was added to dissolve the product. . The mixture was filtered through celite, the organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was dissolved in a minimal amount of CHCl ₃ and passed through silica. The solvent was evaporated and the residue was first purified by crystallization from a mixture of CHCl ₃ / PE (petroleum ether) (98/2). The filtrate was purified using Combiflash chromatography (40 g column, 13 g silica, gradient elution from PE to 9/1 PE / EtOAc) and the title compound was obtained as a pale yellow solid, which was purified by washing with PE, and finally a white solid (5.15 g) was obtained. This solid was the last time to be cleaned by drying in vacuo at 80 ° C overnight. In conclusion, the pure expected compound was obtained as an almost white solid in 59% yield (3.6 g); t _square = 123-124 ° C; ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.13 (1H, td, J = 2.5 and 7.3 Hz, ArH), 7.30 (1H, t, J = 7.7 Hz, ArH) 7.40 (1H, t, J = 7.7 Hz, ArH), 7.56 (1H, d, J = 7.7 Hz, ArH), 7.69 (1H, d, J = 7.7 Hz, ArH), 7.76-7.86 (3H, m, ArH); Analysis: Calculated for C ₁₅ H ₈ FNO: C 75.94, H 3.40, N 5.90. Found: C 75.70, H 3.37, N 5.97%.

4- (4H-1,2,4-Triazol-4-ylamino) -2- (benzofuran-2-yl) benzonitrile (AUP01171-1)

To a solution of 4H-1,2,4-triazole-4-amine (0.709 g, 8.435 mmol) in DMSO (10 ml) was added KOtBu (0.946 g, 8.435 mmol). The mixture was stirred at RT for 30 minutes, then AUP01158-1 (1.0 g, 4.22 mmol) was added and stirring was continued for 1 hour. The mixture was poured onto crushed ice and neutralized with a 2M KHSO ₄ solution (4 ml). The precipitate was filtered off, washed with water (5 × 20 ml) and dried (P ₂ O ₅ ). The solid was washed with acetone (20 ml) and the filtrate was purified using Combiflash chromatography (24 g column, 5 g silica, gradient elution from a 6/4 CHCl ₃ / acetone mixture to acetone in 25 min) and the desired compound was obtained in as a white solid (990 mg, 78%); t _square = 278-279 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 6.55 (1H, dd, J = 2.2 and 8.7 Hz, ArH), 7.11 (1H, d, J = 2.2 Hz, ArH), 7.32 (1H, t, J = 7.5 Hz, ArH), 7.41 (1H, t, J = 7.0 Hz, ArH), 7.66 (1H, d, J = 8 , 3 Hz, ArH), 7.68 (1H, s, ArH), 7.80 (1H, d, J = 7.4 Hz, ArH), 7.85 (1H, d, J = 8.5 Hz , ArH), 8.90 (2H, s, ArH), 10.40 (1H, broad s, NH); Analysis: Calculated for CpHnNsO: C 67.77, H 3.68, N 23.24. Found: C, 67.90; H, 3.64; N, 22.80%.

2- (Benzofuran-2-yl) -4 - ((4- (benzyloxy) benzyl) (4H-1,2,4-triazol-4-yl) amino) benzonitrile (AUP01174-1)

To a solution of compound AUP01171-1 (603 mg, 2.0 mmol) in DMF (10 ml) at 0 ° C was added NaH (82 mg, 2.04 mmol) and the mixture was stirred at RT for 30 min. Then 4-benzyloxybenzyl chloride (466 mg, 2.0 mmol) was added and stirring was continued for 18 hours. The reaction mixture was diluted with EtOAc (30 ml), washed with water (3 × 30 ml) and brine (30 ml), dried ( Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified using Combiflash chromatography (column 24 g, silica 5 g, elution in a gradient mode from CHCl ₃ to a mixture of CHCl ₃ / acetone composition 8/2 in 25 min) and after washing with MeOH, the desired compound was obtained as a white solid substances (825 mg, 83%); t _square = 200-201 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 5.06 (2H, s, CH ₂ ), 5.08 (2H, s, CH ₂ ), 6.76 (1H, dd, J = 2.2 and 8.5 Hz, ArH), 6.97 (2H, d, J = 8.8 Hz, ArH), 7.24-7.42 (10H, m, ArH), 7.64 (1H, d, J = 8.0 Hz, ArH), 7.71 (1H, s, ArH), 7.79 (1H, d, J = 7.4 Hz, ArH), 7.91 (1H, d, J = 8 8 Hz, ArH); 8.81 (2H, s, ArH); MCBP (ESI (electrospray ionization)): calculated for C ₃₁ H ₂₄ N ₅ O ₂ (M + H) ⁺ 498.1925, found: 498.1920.

2- (Benzofuran-2-yl) -4 - ((4-hydroxybenzyl) (4H-1,2,4-triazol-4-yl) amino) benzonitrile (AUP01176-1)

Palladium on charcoal (5%, 20 mg) was added to a solution of compound AUP01174-1 (746 mg, 1.50 mmol) in THF (25 ml) and MeOH (25 ml). The solution was stirred in an H ₂ atmosphere (fed from a balloon) overnight. Excess H ₂ was removed and the reaction mixture was filtered through celite, washing with CH ₂ Cl ₂ / MeOH (8/2), then the solvent was removed in vacuo. The solid was washed with MeOH (10 ml) to obtain the desired compound as a white solid (527 mg, 86%); t _square = 222-223 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 5.01 (2H, s, CH ₂ ), 6.68 (2H, d, J = 8.5 Hz, ArH), 6.77 (1H, dd , J = 2.5 and 8.8 Hz, ArH), 7.10 (2H, d, J = 8.5 Hz, ArH), 7.29-7.41 (3H, m, ArH), 7, 64 (1H, d, J = 8.0 Hz, ArH), 7.71 (1H, s, ArH), 7.80 (1H, d, J = 7.7 Hz, ArH), 7.91 (1H d, J = 8.8 Hz, ArH), 8.76 (2H, s, ArH), 9.53 (1H, broad s, OH); HRMS (ESI): calculated for C ₂₄ H ₁₈ N ₅ O ₂ (M + H) ⁺ 408.1455, found: 408.1450.

4 - (((3- (Benzofuran-2-yl) -4-cyanophenyl) (4H-1,2,4-triazol-4-yl) amino) methyl) phenyl sulfamate (AUP01181-1)

A solution of sulfamoyl chloride in toluene (0.5 M, 4.0 ml) was concentrated in vacuo at 30 ° C to give a yellow oil, which solidified upon cooling in an ice bath. Then, DMA (2.0 ml) and compound AUP01176-1 (203 mg, 0.5 mmol) were added and the mixture was allowed to warm to room temperature and was stirred overnight. The resulting solution was added to brine (20 ml) and the product was extracted with EtOAc (20 ml × 5). The organic layers were combined, washed with brine (20 ml × 3), dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo. Purification of the crude material by washing with cold MeOH afforded the title compound as a white solid (210 mg, 86%); t _square = 202-203 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 5.21 (2H, s, CH ₂ ), 6.75 (1H, dd, J = 2.8 and 8.8 Hz, ArH), 7.24 -7.47 (7H, t, ArH), 7.64 (1H, d, J = 8.0 Hz, ArH), 7.70 (1H, s, ArH), 7.80 (1H, d, J = 7.7 Hz, ArH), 7.93 (1H, d, J = 8.8 Hz, ArH), 8.05 (2H, broad s, NH ₂ ), 8.90 (2H, s, ArH _triazole ); MCBP (ESI): calculated for C ₂₄ H ₁₉ N ₆ O ₄ S (M + H) ⁺ 487.1183, found: 487.1167.

2- (Benzofuran-2-yl) -4 - ((3-chloro-4-hydroxybenzyl) (4H-1,2,4-triazol-4-yl) amino) benzonitrile (AUP01177-1)

A solution of 2-chloro-4- (hydroxymethyl) phenol (САВ06028) (317 mg, 2.00 mmol) in SOCl ₂ (7 ml) was stirred at RT for 30 min. Excess SOCl ₂ was removed under reduced pressure (in a rotary evaporator) and the residue was dissolved in DMF (7 ml). Then, AUP01171-1 (603 mg, 2.00 mmol) and K ₂ CO ₃ (1.84 g, 13.37 mmol) were added and the mixture was stirred overnight. EtOAc (30 ml) and 2M KHS04 solution (10 ml to pH = 4-5) were added, the organic layer was separated, washed with water (20 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure . The solid was purified by washing with hot IPA (propan-2-ol, isopropyl alcohol) (6 ml) and thoroughly sonicated to give the title compound as a white solid (651 mg). The filtrate was purified using Combiflash chromatography (column 12 g, silica 3 g, elution in a gradient mode from a mixture of CHCl ₃ / acetone composition 9/1 to acetone in 15 min) and the desired compound was obtained as a white solid (40 mg). In conclusion, compound AUP01177-1 was obtained in 78% yield (691 mg); t _square = 196-197 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 5.03 (2H, s, CH ₂ ), 6.75 (1H, dd, J = 2.5 and 8.8 Hz, ArH), 6.88 (1H, d, J = 8.3 Hz, ArH), 7.07 (1H, dd, J = 1.9 and 8.3 Hz, ArH), 7.26-7.45 (4H, m, ArH ), 7.64 (1H, d, J = 8.0 Hz, ArH), 7.71 (1H, s, ArH), 7.80 (1H, d, J = 7.7 Hz, ArH), 7 92 (1H, d, J = 8.8 Hz, ArH); 8.83 (2H, s, ArH); 10.33 (1H, broad s, OH); HRMS (ESI): calculated for C ₂₄ H ₁₇ ClN ₅ O2 (M + H) ⁺ 442.1065, found: 442.1059.

4 - (((3- (Benzofuran-2-yl) -4-cyanophenyl) (4H-1,2,4-triazol-4-yl) amino) methyl) -2-chlorophenyl sulfamate (AUP01184-1)

A solution of sulfamoyl chloride in toluene (0.5 M, 4.0 ml) was concentrated in vacuo at 30 ° C to give a yellow oil, which solidified upon cooling in an ice bath. Then, DMA (2.0 ml) and compound AUP01177-1 (221 mg, 0.5 mmol) were added and the mixture was allowed to warm to room temperature and was stirred overnight. The resulting solution was added to brine (20 ml) and the product was extracted with EtOAc (20 ml × 10). The organic layers were combined, washed again with brine (20 ml × 3) and the solvent was removed in vacuo. Purification of the crude material by washing with cold MeOH afforded the title compound as a white solid (226 mg, 87%); t _square = 214-215 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 5.21 (2H, s, CH ₂ ), 6.74 (1H, dd, J = 2.7 and 8.8 Hz, ArH), 7.25 (1H, d, J = 2.5 Hz, ArH), 7.33 (1H, t, J = 7.2 Hz, ArH), 7.39-7.49 (3H, m, ArH), 7, 63 (1H, d, J = 8.5 Hz, ArH), 7.65 (1H, s, ArH), 7.70 (1H, s, ArH), 7.80 (1H, d, J = 7, 7 Hz, ArH), 7.94 (1H, d, J = 8.8 Hz, ArH), 8.32 (2H, broad s, NH ₂ ), 8.96 (2H, s, ArH _triazole ); HRMS (ESI): calculated for C ₂₄ H ₁₈ ClN ₆ O ₄ S (M + H) ⁺ 521.0793, found: 521.0788.

2- (Benzofuran-2-yl) -4 - ((3-bromo-4-hydroxybenzyl) (4H-1,2,4-triazol-4-yl) amino) benzonitrile (AUP01189-1)

A solution of 2-bromo-4- (hydroxymethyl) phenol (203 mg, 1.00 mmol) in SOCl ₂ (3.5 ml) was stirred at RT for 30 minutes. Excess SOCl ₂ was removed under reduced pressure (using a vacuum pump) and the residue was dissolved in DMF (3.5 ml). Then, AUP01171-1 (301 mg, 1.00 mmol) and K ₂ CO ₃ (921 mg, 6.67 mmol) were added and the mixture was stirred overnight. EtOAc (30 ml) and a 2M KHSO ₄ solution (5 ml to pH = 4-5) were added, the organic layer was separated, washed with water (20 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude material was purified using Combiflash chromatography (column 24 g, silica 8 g, elution in a gradient mode from CHCl ₃ to acetone in 30 min) and the desired compound was obtained as a white solid (211 mg after washing with cold MeOH, 43%) and the starting material was recovered as a white solid (88 mg, 29%); t _square = 147-148 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 5.03 (2H, s, CH ₂ ), 6.75 (1H, dd, J = 2.8 and 8.7 Hz, ArH), 6.87 (1H, d, J = 8.3 Hz, ArH), 7.11 (1H, dd, J = 1.9 and 8.2 Hz, ArH), 7.30-7.48 (4H, m, ArH ), 7.64 (1H, d, J = 8.3 Hz, ArH), 7.71 (1H, s, ArH), 7.80 (1H, d, J = 7.7 Hz, ArH), 7 92 (1H, d, J = 8.8 Hz, ArH), 8.83 (2H, s, ArH _triazole ), 10.40 (1H, broad s, OH); HRMS (ESI): calculated for C ₂₄ H ₁₇ BrN ₅ O ₂ (M + H) ⁺ 486.0560, found: 4486.0562.

4 - (((3- (Benzofuran-2-yl) -4-cyanophenyl) (4H-1,2,4-triazol-4-yl) amino) methyl) -2-bromophenyl sulfamate (AUP01185-1)

A solution of sulfamoyl chloride in toluene (0.5 M, 7.73 ml) was concentrated in vacuo at 30 ° C to give a yellow oil, which solidified upon cooling in an ice bath. Then, DMA (4.0 ml) and compound AUP01189-1 (470 mg, 0.97 mmol) were added and the mixture was allowed to warm to room temperature and was stirred overnight. The resulting solution was added to brine (20 ml) and the product was extracted with EtOAc (20 ml × 5). The organic layers were combined, washed with brine (20 ml × 3), dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo. The crude material was purified using Combiflash chromatography (column 24 g, silica 5 g, elution in a gradient mode from CHCl ₃ to acetone in 30 min) to obtain the desired compound as a pale yellow solid, which was purified by washing with cold MeOH, and the title compound was obtained as a white solid (198 mg, 36%); t _square = 199-200 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 5.21 (2H, s, CH ₂ ), 6.73 (1H, dd, J = 2.7 and 8.8 Hz, ArH), 7.26 (1H, d, J = 2.5 Hz, ArH), 7.33 (1H, t, J = 7.2 Hz, ArH), 7.42 (1H, t, J = 7.7 Hz, ArH) 7.44-7.47 (2H, m, ArH), 7.64 (1H, d, J = 8.0 Hz, ArH), 7.70 (1H, s, ArH), 7.78 (1H , s, ArH), 7.80 (1H, d, J = 8.5 Hz, ArH), 7.94 (1H, d, J = 8.8 Hz, ArH), 8.32 (2H, broad s , NH ₂ ), 8.96 (2H, s, ArH _triazole ); HRMS (ESI): calculated for C ₂₄ H ₁₈ BrN ₆ O ₄ S (M + H) ⁺ : 565.0288, found: 565.0296.

4-Fluoro-2- (furan-2-yl) benzonitrile (AUP01160-1)

Following a procedure similar to that described for the preparation of compound AUP01158-1, compound AUP01160-1 was prepared from 2-bromo-4-fluorobenzonitrile (5.0 g, 25.0 mmol), furan-2-ylboronic acid (3.36 g, 30 , 0 mmol), Pd ₂ (dba) ₃ (100 mg), 1,2-dimethoxyethane (25 ml) and 2M Na ₂ CO ₃ solution (40 ml). The crude material was purified by Combiflash chromatography (24 g column, 8 g silica, gradient elution from PE to 9/1 PE / EtOAc) and the title compound was obtained as a light yellow solid. This solid was the last time to be cleaned by drying in vacuo at 40 ° C for 5 days. In conclusion, a supposedly pure compound was obtained as an almost white solid in 35% yield (1.65 g); t _square = 55-56 ° C; ¹ H NMR (270 MHz, CDCl ₃ ) δ 6.58-6.59 (1H, m, ArH), 7.02 (1H, td, J = 2.7 and 8.0 Hz, ArH), 7, 40 (1H, d, J = 3.6 Hz, ArH), 7.57 (1H, s, ArH), 7.62 (1H, d, J = 2.7 Hz, ArH), 7.70 (1H , dd, J = 5.5 and 7.7 Hz, ArH); HRMS (ESI): calculated for C ₁₁ H ₇ FNO (M + H) ⁺ 188.0506, found: 188.0513.

4- (4H-1,2,4-Triazol-4-ylamino) -2- (furan-2-yl) benzonitrile (AUPO 1173-1)

According to a procedure similar to that described for the preparation of compound AUP01171-1, compound AUP01173-1 was obtained from 4H-1,2,4-triazole-4-amine (1.66 g, 19.8 mmol), KOtBu (2.22 g, 19.8 mmol), compounds AUP01160-1 (1.85 g, 9.88 mmol) and DMSO (23 ml). The mixture was poured onto crushed ice and neutralized with a 2M KHSO ₄ solution (6 ml). The precipitate was filtered off, washed with water (5 × 20 ml) and dried (P ₂ O ₅ ). The solid was washed with acetone (10 ml) and the filtrate was purified using Combiflash chromatography (column 24 g, silica 5 g, elution in a gradient mode from CH ₂ Cl ₂ to MeOH in 25 min) and the desired compound was obtained as a light brown solid substances (1.70 g, 68%); t _square = 217-218 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 6.52 (1H, dd, J = 2.2 and 8.5 Hz, ArH), 6.69-6.71 (1H, m, ArH), 6.84 (1H, d, J = 2.2 Hz, ArH), 7.22 (1H, d, J = 3.6 Hz, ArH), 7.77 (1H, d, J = 8.5 Hz , ArH), 7.89 (1H, d, J = 2.0 Hz, ArH), 8.89 (2H, s, ArH), 10.35 (1H, broad s, NH); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 97.12 (C), 107.87 (CH), 110.58 (CH), 111.38 (CH), 112.51 (CH), 119, 12 (C), 133.79 (C), 136.35 (CH), 144.11 (CH × 2), 144.60 (CH), 148.86 (C), 151.12 (C); HRMS (ESI): calculated for C ₁₃ H ₁₀ N ₅ O (M + H) ⁺ 252.0880, found: 252.0876.

4 - ((4- (Benzyloxy) benzyl) (4H-1,2,4-triazol-4-yl) amino) -2- (furan-2-yl) benzonitrile (AUP02004-1)

To a solution of compound AUP01173-1 (502 mg, 2.0 mmol) in DMF (10 ml) at 0 ° C was added NaH (82 mg, 2.04 mmol) and the mixture was stirred at RT for 30 min. Then 4-benzyloxybenzyl chloride (466 mg, 2.0 mmol) was added and stirring was continued for 18 hours. The reaction mixture was diluted with EtOAc (30 ml), washed with water (3 × 30 ml) and brine (30 ml), dried ( Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified using Combiflash chromatography (column 24 g, silica 5 g, elution in a gradient mode from CHCl ₃ to a mixture of CHCl ₁ / acetone composition 8/2 in 25 min) and after washing with a mixture of PE / EtOAc composition 2/8 received the desired compound as a white solid (661 mg, 74%); t _square = 181-182 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 5.04 (2H, s, CH ₂ ), 5.06 (2H, s, CH ₂ ), 6.70-6.76 (2H, m, ArH ), 6.95 (2H, d, J = 8.5 Hz, ArH), 7.00 (1H, d, J = 2.5 Hz, ArH), 7.21-7.26 (3H, m, ArH), 7.30-7.45 (5H, m, ArH), 7.84 (1H, d, J = 8.8 Hz, ArH), 7.89 (1H, d, J = 1.6 Hz , ArH), 8.78 (2H, s, ArH _triazole ); HRMS (ESI): calculated for C ₂₇ H ₂₂ N ₅ O ₂ (M + H) ⁺ 448.1768, found: 448.1760.

2- (Furan-2-yl) -4 - ((4-hydroxybenzyl) (4H-1,2,4-triazol-4-yl) amino) benzonitrile (AUP02005-1)

Palladium on charcoal (5%, 20 mg) was added to a solution of compound AUP02004-1 (600 mg, 1.34 mmol) in THF (20 ml) and MeOH (20 ml). The solution was stirred in an H ₂ atmosphere (fed from a balloon) overnight. Excess H ₂ was removed and the reaction mixture was filtered through celite, washing with CH ₂ Cl ₂ / MeOH (8/2), then the solvent was removed in vacuo. The solid was washed with MeOH (5 ml) to obtain the desired compound as a white solid (275 mg, 57%); t _square = 218-219 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 4.96 (2H, s, CH2), 6.67 (2H, d, J = 8.3 Hz, ArH), 6.70-6.75 ( 2H, m, ArH), 7.00 (1H, d, J = 2.5 Hz, ArH), 7.07 (2H, d, J = 8.5 Hz, ArH), 7.25 (1H, d , J = 3.6 Hz, ArH), 7.83 (1H, d, J = 8.8 Hz, ArH), 7.89 (1H, d, J = 1.1 Hz, ArH), 8.73 (2H, s, ArH _triazole ), 9.50 (1H, broad s, OH); HRMS (ESI): calculated for C ₂₀ H ₁₆ N ₅ O ₂ (M + H) ⁺ 358.1299, found: 358.1292.

4 - (((4-Cyano-3- (furan-2-yl) phenyl) (4H-1,2,4-triazol-4-yl) amino) methyl) phenyl sulfamate (AUP02011-1)

A solution of sulfamoyl chloride in toluene (0.5 M, 6.7 ml) was concentrated in vacuo at 30 ° C to give a yellow oil, which solidified upon cooling in an ice bath. Then, DMA (1.8 ml) and compound AUP02005-1 (150 mg, 0.42 mmol) were added and the mixture was allowed to warm to room temperature and was stirred overnight. The resulting solution was added to brine (20 ml) and the product was extracted with EtOAc (20 ml × 5). The organic layers were combined, washed with brine (20 ml × 3), dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo. The crude material was purified using Combiflash chromatography (column 12 g, silica 3 g, elution in a gradient mode from CHCl ₃ to acetone in 30 min) to obtain the desired compound as a pale yellow solid, which was purified by washing with cold MeOH, and the title compound was obtained as a white solid (134 mg, 73%); t _square = 177-178 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 5.16 (2H, s, CH ₂ ), 6.70-6.72 (2H, t, ArH), 6.97 (1H, d, J = 2.8 Hz, ArH), 7.23 (1H, d, J = 5.2 Hz, ArH), 7.25 (2H, s, ArH), 7.43 (2H, d, J = 8.5 Hz, ArH), 7.85 (1H, d, J = 8.5 Hz, ArH), 7.90 (1H, d, J = 1.7 Hz, ArH), 8.01 (2H, broad s, NH ₂ ), 8.87 (2H, s, ArH _triazole ); HRMS (ESI): calculated for C ₂₀ H ₁₇ N ₆ O ₄ S (M + H) + 437.1027, found: 437.1028.

Methyl 2,6-difluoro-4-hydroxybenzoate (PMW03136)

SOCl ₂ (4.16 g, 30.1 mmol) was added to a solution of 2,6-difluoro-4-hydroxybenzoic acid (1.50 g, 8.62 mmol) in MeOH (20 ml) and the resulting mixture was refluxed within 24 hours. After cooling, the solvent was removed in vacuo to give the desired compound (1.62 g, 99%) as a white crystalline solid; t _square = 177.5-180 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 3.80 (3H, s, CH ₃ ), 6.50-6.60 (2H, t, ArH), 11.16 (1H, s, OH) .

3,5-Difluoro-4- (hydroxymethyl) phenol (PMW03144)

A solution of compound PMW03136 (1.70 g, 9.14 mmol) in THF (10 ml) was slowly added to a suspension of LiAlH ₄ (1.39 g, 36.6 mmol) in THF (20 ml). After 45 minutes, the reaction was stopped by careful addition of EtOAc (10 ml), H ₂ O (20 ml) and 3M HCl solution (10 ml). The product was extracted with EtOAc (2 × 40 ml) and the combined organics were washed with saturated aqueous NaHCO ₃ (50 ml), dried (MgSO ₄ ) and the solvent was removed in vacuo. The crude product was purified using Flashmaster II (EtOAc / Hexane) to give the title compound (1.03 g, 70%) as a white solid; t _square = 160 ° C (with decomposition); ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 4.36 (1H, d, J = 5.4, CH ₂ ), 5.03 (1H, d, J = 5.4, OH), 6, 39-6.50 (2H, m, ArH); 10.43 (1H, s, OH); LC / MS (liquid chromatography / mass spectrometry) (ER-) t _r (retention time) = 0.90 min, m / z 158.9 (M ^- -1, 100%), 140.9 (60).

5 - ((2,6-Difluoro-4-hydroxybenzyl) (4H-1,2,4-triazol-4-yl) amino) biphenyl-2-carbonitrile (PMW04146)

A solution of compound PMW03144 (0.45 g, 2.81 mmol) in a mixture containing SOCl ₂ (5 ml) / DMF (0.3 ml) was stirred for 2 hours. The solvent was removed in vacuo and the resulting residue was dissolved in DMF ( 10 ml). 5- (4H-1,2,4-triazol-4-ylamino) biphenyl-2-carbonitrile (compound САВ06022) (0.77 g, 2.95 mmol) and K ₂ CO ₃ (1.94 g, 14) were added. , 1 mmol) and the reaction mixture was stirred for 48 h. The mixture was poured into H ₂ O (50 ml) and the product was extracted with EtOAc (2 (50 ml). The combined organics were washed with H ₂ O (4 (50 ml ) and brine (50 ml), then dried (MgSO ₄ ) and the solvent was removed in vacuo. The crude product was purified using the Combiflash system (DCM (dichloromethane) / acetone) to obtain the desired compound as a white solid (0.60 g, 53%); ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 5.06 (2H, s, CH ₂ ), 6.38-6.49 (2H, m, ArH), 6.71 (1H, dd, J = 8.6, 2.2, ArH) 6.83 (1H, d, J = 2.2, ArH), 7.48-7.61 (5H, t, ArH), 7.87 (1H, d, J = 8.6, ArH), 8.75 (2H, s, NCHN); 10.58 (1H, s, OH); HRMS (ER +): calculated for C ₂₂ H ₁₆ F ₂ N ₅ O (M ++ 1) 404.1317, found : 404.1311; LC / MS (ER +) t _r = 1.40 min, m / z 404.1 (M ⁺ -1, 100%).

4 - (((6-Cyanobiphenyl-3-yl) (4H-1,2,4-triazol-4-yl) amino) methyl) -3,5-difluorophenyl sulfamate (PMW04153)

In a rotary evaporator at 30 ° C, the solvent was removed from a solution of ClSO ₂ NH ₂ in toluene (0.57 M, 6.2 ml) to obtain a yellow oil, which solidified upon cooling in an ice bath. Then, DMA (1 ml) and a solution of compound PMW04146 (0.21 g, 0.52 mmol) in DMA (1 ml) were added, and the reaction mixture was stirred overnight. The solution was poured into H ₂ O (15 ml) and the product was extracted with EtOAc (2 × 15 ml). The organic layers were combined, washed with H ₂ O (4 × 15 ml) and brine (15 ml), dried (MgSO ₄ ) and the solvent was removed in vacuo. The crude product was purified using the Combiflash system (CHCl ₃ / acetone) to give the title compound (0.22 g, 88%) as a white solid; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 5.24 (2H, s, CH ₂ ), 6.71 (1H, dd, J = 8.8, 2.8, ArH), 6.88 ( 1H, d, J = 2.8, ArH), 7.05-7.14 (2H, m, ArH), 7.50-7.62 (5H, m, ArH), 7.89 (1H, d J-8.8, ArH), 8.33 (2H, s, NH ₂ ), 8.82 (2H, s, NCHN); MCBP (ER +): calculated for C ₂₂ H ₁₇ F ₂ N ₆ O ₃ S (M ⁺ +1) 483.1045, found: 483.1031; LC / MS (ER +) t _r = 1.06 min, m / z 483.3 (M ⁺ +1, 100%).

4-Fluoro-2- (furan-3-yl) benzonitrile (AUP01162-1)

Following a procedure similar to that described for the preparation of compound AUP0115 8-1, compound AUP01162-1 was prepared from 2-bromo-4-fluorobenzonitrile (5.0 g, 25.0 mmol), furan-3-ylboronic acid (3.36 g, 30.0), Pd ₂ (dba) ₃ (100 mg), 1,2-dimethoxyethane (25 ml) and 2M Na ₂ CO ₃ solution (40 ml). The crude material was purified by Combiflash chromatography (24 g column, 8 g silica, gradient elution from PE to 9/1 PE / EtOAc) and the title compound was obtained as a light yellow solid. This solid was the last time to be cleaned by drying in vacuo at 60 ° C for 3 days. In conclusion, a supposedly pure compound was obtained as an almost white solid in 32% yield (1.47 g); t _square = 42-68 ° C (with decomposition); ¹ H NMR (270 MHz, CDCl ₃ ) δ 6.81 (1H, d, J = 2.0 Hz, ArH), 7.07 (1H, td, J = 2.5 and 8.0 Hz, ArH) 7.24 (1H, dd, J = 2.5 and 8.7 Hz, ArH), 7.52-7.55 (1H, m, ArH), 7.72 (1H, dd, J = 5, 8 and 8.7 Hz, ArH); 8.06 (1H, s, ArH); MCBP (ESI): calculated for C ₁₁ H ₇ FNO (M + H) ⁺ 188.0506, found: 188.0513.

4- (4H-1,2,4-Triazol-4-ylamino) -2- (furan-3-yl) benzonitrile (AUP01172-1)

According to a procedure similar to that described for the preparation of compound AUP01171-1, compound AUP01172-1 was obtained from 4H-1,2,4-triazole-4-amine (1.79 g, 21.4 mmol), KOtBu (2.40 g, 21.4 mmol), compounds AUP01162-1 (2.0 g, 10.70 mmol) and DMSO (25 ml). The mixture was poured onto crushed ice and neutralized with a 2M KHSO ₄ solution (6 ml). The precipitate was filtered off, washed with water (5 × 20 ml) and dried (P ₂ O ₅ ). The solid was washed with acetone (10 ml) and the filtrate was purified using Combiflash chromatography (column 24 g, silica 5 g, elution in a gradient mode from CH ₂ Cl ₂ od MeOH in 25 min) and the desired compound was obtained as a light brown solid substances (2.05 g, 76%); t _square = 199-200 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 6.45 (1H, dd, J = 2.2 and 8.5 Hz, ArH), 6.66 (1H, d, J = 2.2 Hz, ArH), 6.83-6.84 (1H, m, ArH), 7.75 (1H, d, J = 8.5 Hz, ArH), 7.84 (1H, s, ArH), 8.14 (1H, s, ArH), 8.85 (2H, s, ArH), 10.24 (1H, broad s, NH); MCBP (ESI): calculated for C ₁₃ H ₁₀ N ₅ O (M + H) ⁺ 252.0880, found: 258.0872; Analysis: Calculated for C ₁₃ H ₉ N ₅ O: C 62.15, H 3.61, N 27.87. Found: C 61.90, H 3.57, N 27.40%.

4 - ((4- (Benzyloxy) benzyl) (4H-1,2,4-triazol-4-yl) amino) -2- (furan-3-yl) benzonitrile (AUP02018-1)

To a solution of compound AUP01172-1 (502 mg, 2.0 mmol) in DMF (10 ml) at 0 ° C was added NaH (82 mg, 2.04 mmol) and the mixture was stirred at RT for 30 min. Then 4-benzyloxybenzyl chloride (466 mg, 2.0 mmol) was added and stirring was continued for 18 hours. The reaction mixture was diluted with EtOAc (30 ml), washed with water (3 × 30 ml) and brine (30 ml), dried ( Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified using Combiflash chromatography (column 24 g, silica 5 g, elution in a gradient mode from CHCl ₃ to a mixture of CHCl ₃ / acetone composition 8/2 in 25 min) and after washing with a mixture of PE / EtOAc composition 2/8, the desired the compound in the form of a white solid (580 mg, 65%); tnn. = 155-156 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 5.04 (2H, s, CH ₂ ), 5.06 (2H, s, CH 3), 6.49 (1H, dd, J = 2.8, 8.7 Hz, ArH), 6.93-6.97 (3H, m, ArH), 7.05 (1H, d, J = 2.5 Hz, ArH), 7.22 (2H, d, J = 8.5 Hz, ArH), 7.29-7.46 (5H, m, ArH), 7.79 (1H, d, J = 8.8 Hz, ArH), 7.85-7.87 ( 1H, m, ArH), 8.21 (1H, s, ArH), 8.75 (2H, s, ArH _triazole ); HRMS (ESI): calculated for C ₂₇ H ₂₂ N ₅ O ₂ (M + H) ⁺ 448.1768, found: 448.1770; Analysis: Calculated for C ₂₇ H ₂₁ N ₅ O ₂ : C 72.47, H 4.73, N 15.65. Found: C, 72.40; H, 4.73; N, 15.70%.

2- (Furan-3-yl) -4 - ((4-hydroxybenzyl) (4H-1,2,4-triazol-4-yl) amino) benzonitrile (AUP02023-1)

Palladium on charcoal (5%, 20 mg) was added to a solution of compound AUP02018-1 (510 mg, 1.14 mmol) in THF (15 ml) and MeOH (15 ml). The solution was stirred in an H ₂ atmosphere (fed from a balloon) for 5 hours. The excess H ₂ was removed and the reaction mixture was filtered through celite, washing with CH ₂ Cl ₂ / MeOH (8/2), then the solvent was removed in vacuo. The solid was washed with CH ₂ Cl ₂ (5 ml) to give the title compound as a white solid (383 mg, 94%); t _square = 217-218 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 4.97 (2H, s, CH ₂ ), 6.48 (1H, dd, J = 2.5 and 8.5 Hz, ArH), 6.67 (2H, d, J = 8.5 Hz, ArH), 6.94 (1H, d, J = 1.9 Hz, ArH), 7.03-7.09 (3H, m, ArH), 7, 78 (1H, d, J = 8.8 Hz, ArH), 7.84-7.87 (1H, m, ArH), 8.20 (1H, s, ArH), 8.70 (2H, s, _triazol ArH), 9.51 (1H, broad s, OH); HRMS (ESI): calculated for C ₂₀ H ₁₆ N ₅ O ₂ (M + H) ⁺ 358.1299, found: 358.1290; Analysis: Calculated for C ₂₀ H ₁₅ N ₅ O ₂ : C 67.22, H 4.23, N 19.60. Found: C, 67.40; H, 4.25; N, 19.60%.

4 - (((4-Cyano-3- (furan-3-yl) phenyl) (4H-1,2,4-triazol-4-yl) amino) methyl) phenyl sulfamate (AUP02026-1)

A solution of sulfamoyl chloride in toluene (0.5 M, 5.8 ml) was concentrated in vacuo at 30 ° C to give a yellow oil, which solidified upon cooling in an ice bath. Then, DMA (1.8 ml) and compound AUP02023-1 (130 mg, 0.36 mmol) were added and the mixture was allowed to warm to room temperature and was stirred overnight. The resulting solution was added to brine (20 ml) and the product was extracted with EtOAc (20 ml × 5). The organic layers were combined, washed with brine (20 ml × 3), dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo. The crude material was purified by Combiflash chromatography (column of 12 g silica 3 g, eluting with a gradient of CHCl ₃ to acetone for 30 minutes) to give the title compound as a pale yellow solid which was purified by washing with cold CH ₂ Cl ₂ , and the desired compound was obtained as a white solid (129 mg, 81%); t _square = 195-196 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 5.16 (2H, s, CH ₂ ), 6.48 (1H, dd, J = 2.5 and 8.8 Hz, ArH), 6.92 (1H, s, ArH), 6.99 (1H, d, J = 2.5 Hz, ArH), 7.23 (2H, d, J = 8.5 Hz, ArH), 7.42 (2H, d, J = 8.5 Hz, ArH), 7.80 (1H, d, J = 8.5 Hz, ArH), 7.84-7.86 (1H, m, ArH), 8.03 (2H broad s, NH ₂ ), 8.20 (1H, s, ArH), 8.84 (2H, s, ArH _triazole ); MCBP (ESI): calculated for C ₂₀ H ₁₇ N ₆ O ₄ S (M + H) ⁺ 437.1027, found: 437.1018.

4 - ((3-Chloro-4-hydroxybenzyl) (4H-1,2,4-triazol-4-yl) amino) -2- (furan-3-yl) benzonitrile (AUP02020-1)

A solution of 2-chloro-4- (hydroxymethyl) phenol (compound CAV06028) (317 mg, 2.00 mmol) in SOCl ₂ (7 ml) was stirred at RT for 30 minutes. Excess SOC12 was removed under reduced pressure (in a rotary evaporator) and the residue was dissolved in DMF (7 ml). Then, AUP01172-1 (502 mg, 2.00 mmol) and K ₂ CO ₃ (1.84 g, 13.37 mmol) were added and the mixture was stirred overnight. EtOAc (30 ml) and a 2M KHSO ₄ solution (10 ml to pH = 4-5) were added, the organic layer was separated, washed with water (20 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified twice using Combiflash chromatography (column 24 g, silica 8 g, elution in a gradient mode from CHC1z to acetone in 40 min) and after washing with a PE / EtOAc mixture of 2/8, the desired compound was obtained as a white solid (355 mg, 45%); t _square = 192-193 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 4.99 (2H, s, CH ₂ ), 6.48 (1H, dd, J = 2.5 and 8.8 Hz, ArH), 6.87 (1H, d, J = 8.5 Hz, ArH), 6.94-7.05 (3H, m, ArH), 7.29 (1H, d, J = 1.9 Hz, ArH), 7, 79 (1H, d, J = 8.8 Hz, ArH), 7.85-7.87 (1H, m, ArH), 8.21 (1H, s, ArH), 8.77 (2H, s, ArH _triazole ), 10.34 (1H, broad s, OH); HRMS (ESI): calculated for C ₂₀ H ₁₅ ClN ₅ O ₂ (M + H) ⁺ 392.0909, found: 392.0899.

2-Chloro-4 - (((4-cyano-3- (furan-3-yl) phenyl) (4H-1,2,4-triazol-4-yl) amino) methyl) yenyl sulfamate (AUP02024-1)

A solution of sulfamoyl chloride in toluene (0.5 M, 4.50 ml) was concentrated in vacuo at 30 ° C to give a yellow oil, which solidified upon cooling in an ice bath. Then, DMA (1.2 ml) and compound AUP02020-1 (110 mg, 0.28 mmol) were added and the mixture was allowed to warm to room temperature and was stirred overnight. The resulting solution was added to brine (20 ml) and the product was extracted with EtOAc (20 ml × 5). The organic layers were combined, washed with brine (20 ml × 3), dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo. The crude material was purified using Combiflash chromatography (column 12 g, silica 3 g, elution in a gradient mode from CHCl ₃ to acetone in 30 min) and the desired compound was obtained as a pale yellow solid, which was purified by washing with cold CH ₂ Cl ₂ , and the desired compound was obtained as a white solid (88 mg, 67%); t _square = 154-155 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 5.17 (2H, s, CH ₂ ), 6.48 (1H, dd, J = 2.8 and 8.8 Hz, ArH), 6.92 (1H, s, ArH), 6.99 (1H, d, J = 2.5 Hz, ArH), 7.38-7.47 (2H, m, ArH), 7.60 (1H, s, ArH ), 7.81 (1H, d, J = 8.8 Hz, ArH), 7.86 (1H, s, ArH), 8.19 (1H, s, ArH), 8.31 (2H, broad s , NH ₂ ), 8.90 (2H, s, ArH _triazole ); HRMS (ESI): calculated for C ₂₀ H ₁₆ ClN ₆ O ₄ S (M + H) + 471.0637, found: 471.0638.

4 - ((3-Bromo-4-hydroxybenzyl) (4H-1,2,4-triazol-4-yl) amino) -2- (furan-3-yl) benzonitrile (AUP02028-1)

A solution of 2-bromo-4- (hydroxymethyl) phenol (406 mg, 2.00 mmol) in SOCl ₂ (7 ml) was stirred at RT for 30 minutes. Excess SOC ^ was removed under reduced pressure (using a vacuum pump) and the residue was dissolved in DMF (7 ml). Then, AUP01172-1 (502 mg, 2.00 mmol) and K ₂ CO ₃ (1.84 g, 13.33 mmol) were added and the mixture was stirred overnight. EtOAc (30 ml) and a 2M KHSO ₄ solution (10 ml to pH = 4-5) were added, the organic layer was separated, washed with water (20 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude material was purified using Combiflash chromatography (column 40 g, silica 15 g, elution in a gradient mode from CHCl ₃ to acetone in 30 min) and the desired compound was obtained as a pale orange solid (AUP02028-1: 340 mg after washing cold DCM, 39%) and the starting material as an orange solid (AUP02028-2: 220 mg, 44%); t _square = 200-201 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 4.99 (2H, s, CH ₂ ), 6.48 (1H, dd, J = 2.5 and 8.8 Hz, ArH), 6.86 (1H, d, J = 8.3 Hz, ArH), 6.94 (1H, s, ArH), 7.04-7.10 (2H, m, ArH), 7.43 (1H, s, ArH ), 7.79 (1H, d, J = 8.5 Hz, ArH), 7.86 (1H, s, ArH), 8.21 (1H, s, ArH), 8.76 (2H, s, ArH _triazole ), 10.37 (1H, broad s, OH); HRMS (ESI): calculated for C ₂₀ H ₁₅ BrN ₅ O ₂ (M + H) ⁺ 436.0404, found: 436.0398.

2-Bromo-4 - (((4-cyano-3- (furan-3-yl) phenyl) (4H-1,2,4-triazol-4-yl) amino) methyl) phenyl sulfamate (AUP02030-1)

A solution of sulfamoyl chloride in toluene (0.5 M, 5.1 ml) was concentrated in vacuo at 30 ° C to give a yellow oil, which solidified upon cooling in an ice bath. Then, DMA (1.5 ml) and compound AUP02028-1 (140 mg, 0.32 mmol) were added and the mixture was allowed to warm to room temperature and was stirred overnight. The resulting solution was added to brine (20 ml) and the product was extracted with EtOAc (20 ml × 5). The organic layers were combined, washed with brine (20 ml × 3), dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo. The crude material was purified using Combiflash chromatography (column 12 g, silica 3 g, elution in a gradient mode from CHCl ₃ to acetone in 30 min) and the desired compound was obtained as a pale yellow solid, which was purified by washing with cold CH ₂ Cl ₂ , and the desired compound was obtained as a white solid (114 mg, 69%); t _square = 167-177 ° C (with decomposition); ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 5.17 (2H, s, CH ₂ ), 6.47 (1H, dd, J = 2.5 and 8.8 Hz, ArH), 6.92 (1H, s, ArH), 6.99 (1H, d, J = 2.5 Hz, ArH), 7.44 (2H, s, ArH), 7.74 (1H, s, ArH), 7, 81 (1H, d, J = 8.8 Hz, ArH), 7.86 (1H, s, ArH), 8.19 (1H, s, ArH), 8.32 (2H, broad s, NHa), 8.89 (2H, s, ArH _triazole ); HRMS (ESI): calculated for C ₂₀ H ₁₆ BrN ₆ O ₄ S (M + H) ⁺ 515.0132, found: 515.0139; HPLC (high performance liquid chromatography) (90% CH ₃ CN in H ₂ O) t _r = 1.33 min (100%); Analysis: Calculated for C ₂₀ H ₁₅ BrN ₆ O ₄ S: C 46.61, H 2.93, N 16.31. Found: C 47.00, H 3.10, N 16.00%.

2- (2,6-Difluoro-4-methoxyphenyl) malonic acid (PMW04138)

A 3M aqueous NaOH solution (80 ml) was added to a solution of diethyl 2- (2,6-difluoro-4-methoxyphenyl) malonate (6.30 g, 20.85 mmol) in Et ₂ O (5 ml). The reaction mixture was refluxed until the solid was completely dissolved. After cooling, the mixture was acidified with 3M aqueous HCl and the product was extracted with EtOAc (2 × 100 ml). The combined organic layers were dried (MgSO ₄ ) and the solvent was removed in vacuo to give the title compound as a tan solid (4.50 g, 88%); t _square = 157 ° C (with decomposition); ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 3.78 (3H, s, CH ₃ ), 4.72 (1H, s, CH), 6.70-6.79 (2H, m, ArH) .

2- (2,6-Difluoro-4-methoxyphenyl) acetic acid (PMW04140)

Compound PMW04138 (4.49 g, 18.3 mmol) was heated at 160 ° C. until melting was complete and foaming stopped. After cooling, the product was recrystallized from a mixture of PE / EtOAC and the desired compound was obtained as a white crystalline solid (3.43 g, 93%); t _square = 137-139 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 3.52 (2H, s, CH ₂ , 3.77 (3H, s, CH ₃ ), 6.68-6.79 (2H, m, ArH) ; HRMS (ER +): calculated for C ₉ H ₉ F ₂ O ₂ : 203.0514, found: 203.0508.

Methyl 2- (2,6-difluoro-4-methoxyphenyl) acetate (PMW04141)

A solution of compound PMW04140 (3.37 g, 16.7 mmol) in MeOH (70 ml) containing concentrated HCl (15 drops) was refluxed overnight. The mixture was allowed to cool and was neutralized with a saturated aqueous solution of NaHCO ₃ . The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 ml) and washed with H ₂ O (100 ml), saturated aqueous NaHCO ₃ (100 ml) and brine (100 ml), then dried (MgSO ₄ ) and the solvent was removed in a vacuum. The title compound (3.30 g, 92%) was obtained as a pale yellow oil; H NMR (270 MHz, DMSO-d ₆ ) δ 3.61 (2H, s, CH ₂ ), 3.69 (3H, s, CH ₃ ), 3.76 (3H, s, CH ₃ ), 6, 40-6.49 (2H, m, ArH); ¹⁹ F NMR (376.4 MHz, DMSO-d ₆₎ -114,4 (d); MCBP (ER +): calculated for C ₁₀ H ₁₁ F ₂ O ₃ (M ⁺ + H) 217.0657, found: 217.0663; LC / MS (ER +) t _r = 1.69 min, m / z 216.8 (M ⁺ , 100%).

Methyl 2- (2,6-difluoro-4-hydroxyphenyl) acetate (PMW04148)

BBr ₃ (1 M solution in DCM, 55 ml, 55 mmol) was added to a cooled (-78 ° C) solution of compound PMW04141 (2.87 g, 13.3 mmol) in DCM (25 ml). The reaction mixture was stirred at -78 ° C for 10 min, then it was allowed to warm to room temperature and it was stirred for 3 hours 30. The reaction was stopped with saturated aqueous NaHCO ₃ and the product was extracted with DCM (2 × 150 ml). The combined organic layers were washed with brine (150 mL), dried (MgSO ₄₎ and the solvent removed in vacuo. The crude product was purified using the Combiflash system (PE / EtOAc) to give the title compound (2.07 g, 77%) as a white crystalline solid; t _square = 75.5-77.5 ° C; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 3.58 (2H, s, CH ₂ ), 3.61 (3H, s, CH ₃ ), 6.41-6.51 (2H, m, ArH ), 10.34 (1H, s, OH); ¹⁹ F NMR (376.4 MHz, DMSO-d ₆ ) -115.4 (d); MCBP (ER +): calculated for C ₉ H ₉ F ₂ O ₃ (M ⁺ + H) 203.0514, found: 203.0511; LC / MS (ES +) t _r = 1,45 min, m / z 202,8 (M ⁺ H +, 100%).

Methyl 2- (2,6-difluoro-4- (triisopropylsilyloxy) phenyl) acetate (PMW04151)

Imidazole (1.43 g, 21.0 mmol) and TIPS-Cl (TIPS = triisopropylsilyl, 2.24 g, 11.6 mmol) were successively added to a pale yellow solution of compound PMW041448 (2.13 g, 10.5 mmol) ) in DMF (10 ml). The reaction mixture was stirred overnight, then poured into H ₂ O (40 ml) and extracted with EtOAc (3 (50 ml). The combined organics were washed with H ₂ O (3 (100 ml) and brine (100 ml) , then dried (MgSO ₄ ) and the solvent was removed in vacuo. The crude product was purified using the Combiflash system (PE / EtOAc) to obtain the desired compound as a colorless oil (3.43 g, 91%); ¹ H NMR (270 MHz, CDCl ₃ ) δ 1.04-1.32 (21H, m, 6 × CH ₃ , 3 × CH), 3.60 (2H, s, CH ₂ ), 3.69 (3H, s, CH ₃ ), 6.36-6.48 (2H, m, ArH); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 12.5 (3 × CH), 17.8 (6 × CH ₃ ), 27.4 (CH ₂ ), 52.2 (CH ₃ ), 103.3 (C, t), 103.4 (2 × CH, dd), 156.7 (C, t), 161.6 (2 × C, dd), 170.6 (C); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) -117.9 (d).

2- (2,6-Difluoro-4- (triisopropylsilyloxy) phenyl) ethanol (PMW04155)

A solution of compound PMW04151 (2.98 g, 8.30 mmol) in THF (15 ml) was added to a cooled (0 ° C) suspension of LiAlH ₄ (0.79 g, 20.8 mol) in THF (50 ml). After stirring for 15 minutes, the reaction was stopped by adding EtOAc (25 ml), H ₂ O (25 ml) and 3M HCl solution (25 ml). The product was extracted with EtOAc (2 × 75 ml) and the combined organics were washed with saturated aqueous NaHCO 3 (2 × 100 ml), dried (MgSO ₄ ) and the solvent was removed in vacuo. The crude product was purified using a Combiflash system (EtOAc / PE) to give the title compound (1.70 g, 62%) as a colorless oil; ¹ H NMR (270 MHz, CDCl ₃ ) δ 1.02-1.31 (21H, m, 6 × CH ₃ , 3 × CH), 1.61 (1H, s, OH), 2.85 (2H, t, J = 6,9, CH _2), 3.76 (2H, t, J = 6,9, CH _2), 6,34-6,48 (2H, m, ArH); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) -116.0 (d); MCBP (ER +): calculated for C ₁₇ H ₂₉ F ₂ O ₂ Si (M ⁺ +1) 331.1899, found: 331.1887; LC / MS (ER +) t _r = 2.23 min, m / z 353.4 (M ⁺ + Na, 100%), 331.3 (M ⁺ +1, 80).

(4- (2-Bromoethyl) -3,5-difluorophenoxy) triisopropylsilane (PMW04158)

PPh ₃ (1.11 g, 4.24 mmol) was added to a chilled (0 ° C) solution of CBg4 (0.92 g, 2.77 mmol) in DCM (15 ml). After stirring for 15 min, a solution of compound PMW04155 (0.70 g, 2.12 mmol) in DCM (5 ml) was added and the reaction mixture was stirred for 1 h, then it was allowed to warm to room temperature and it was stirred for 2 h The solvent was removed in vacuo and the residue was purified using the Combiflash system (EtOAc / PE) to give the title compound (0.56 g, 67%) as a colorless oil; ¹ H NMR (270 MHz, CDCl ₃ ) δ 1.05-1.32 (21H, m, 6 × CP ₃ , 3 × CP), 3.13 (2H, t, J = 7.7, CH ₂ ) 3.48 (2H, t, J = 7.7, CH ₂ ); 6.34-6.45 (2H, m, ArH).

5 - ((2,6-Difluoro-4-hydroxyphenethyl) (4H-1,2,4-triazol-4-yl) amino) biphenyl-2-carbonitrile (PMW04165)

NaH (60% dispersion in mineral oil, 0.039 g, 0.98 mmol) was added to a solution of 5- (4H-1,2,4-triazol-4-ylamino) biphenyl-2-carbonitrile (compound САВ06022) (0.23 g, 0.88 mmol) in DMF (5 ml). After stirring for 30 minutes, a solution of compound PMW04158 (0.38 g, 0.97 mmol) in DMF (3 ml) was added and stirring was continued for 48 hours. TBAF (tetrabutylammonium fluoride) (1 M solution in THF, 1.35 ml was added). ) and after 30 minutes the reaction mixture was poured into H ₂ O (15 ml) and acidified with 3M aqueous AcOH. The product was extracted with EtOAc (3 × 25 ml) and the combined organics were washed with H ₂ O (4 × 50 ml) and brine (50 ml), then dried (MgSO ₄ ) and the solvent was removed in vacuo. The crude product was purified using the Combiflash system (CHCl ₃ / acetone) to give the title compound (0.18 g, 50%) as a white solid; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 2.81 (2H, t, J = 7.5, CH ₂ ), 4.01 (2H, t, J = 7.5, CH ₂ ), 6 41-6.51 (3H, m, ArH), 6.61 (1H, d, J = 2.2, ArH), 7.45-7.56 (5H, m, ArH), 7.83 ( 1H, d, J = 8.8, ArH), 8.93 (2H, s, NCHN), 10.40 (1H, s, OH); HRMS (ER +): calculated for C ₁₃ H ₁₈ F ₂ N ₅ O ₁ (M ⁺ +1) 418.1474, found: 418.1466; LC / MS (3P +) t _r = 1.39 min, m / z 418.0 (M ⁺ +1, 100%).

4- (2 - ((6-Cyanobiphenyl-3-yl) (4H-1,2,4-triazol-4-yl) amino) ethyl) -3,5-difluorophenyl sulfamate (PMW04169)

In a rotary evaporator at 30 ° C., the solvent was removed from a solution of ClSO ₂ NH ₂ in toluene (0.45 M, 3.0 ml) to give a yellow oil, which solidified upon cooling in an ice bath. Then, DMA (1 ml) and a solution of compound PMW04165 (0.10 g, 0.24 mmol) in DMA (1 ml) were added and the reaction mixture was stirred overnight. The solution was poured into H ₂ O (15 ml) and the product was extracted with EtOAc (2 × 15 ml). The organic layers were combined, washed with H ₂ O (4 × 15 ml) and brine (15 ml), dried (MgSO ₄ ) and the solvent was removed in vacuo. The crude product was purified using the Combiflash system (CHCl ₃ / acetone) to give the title compound (0.072 g, 61%) as a white solid; ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 2.94 (2H, t, J = 7.4, CH ₂ ), 4.10 (2H, t, J = 7.4, CH ₂ ), 6 51 (1H, dd, J = 8.8, 2.5, ArH), 6.68 (1H, d, J = 2.5, ArH), 7.05-7.13 (2H, m, ArH ), 7.46-7.56 (5H, m, ArH), 7.85 (1H, d, J = 8.8, ArH), 8.25 (2H, s, NH ₂ ), 8.98 ( 2H, s, NCHN); MCBP (ER +): calculated for C ₂₃ H ₁₉ F ₂ N ₆ O ₃ S (M ⁺ +1) 497.1202, found: 497.1200; LC / MS (ER +) t _r = 1.31 min, m / z 497.3 (M ⁺ +1, 100%).

5-Fluoro-4 '- (trifluoromethyl) biphenyl-2-carbonitrile (САВ06081)

A mixture of 2-bromo-4-fluorobenzonitrile (4.0 g, 20.0 mmol), 4- (trifluoromethyl) phenylboronic acid (4.178 g, 22.0 mmol), dimethoxyethane (30 ml) and a 2M solution of Na ₂ CO ₃ ( 40 ml) was refluxed, then Pd ₂ (dba) ₃ (0.10 g) was added and heating was continued for 5 hours. After cooling to room temperature, CHCl ₃ (50 ml) was added and the mixture was filtered (through celite). The organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified using flash chromatography [SiO ₂ , CHCl ₃ ], then recrystallized from a mixture of CHCl ₃ / n-hexane and received the connection CAV06081 (4.03 g, 71%) as colorless needles, t _pl. = 106-107 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.53 (dt, J = 8.6, 2.7 Hz, 1H), 7.62 (dd, J = 9.8, 2.7 Hz, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H), 8.11 (dd, J = 8.6, 5.5 Hz, 1H); LRMS (ES +): m / z 266,1 ^{(100%, [M + H] +} ); MCBP (ER +): calculated for C ₁₄ H ₈ F ₄ N [M + H] ⁺ : 266.0587, found: 266.0577; Analysis: Calculated for C ₁₄ H ₈ F ₄ N: C, 63.40; H, 2.66; N, 5.28. Found: C, 63.5; H, 2.66; N, 5.28.

5- (4H-1,2,4-Triazol-4-ylamino) -4 '- (trifluoromethyl) biphenyl-2-carbonitrile (САВ06082)

To a solution of 4H-1,2,4-triazole-4-amine (1.322 g, 15.84 mmol) in DMSO (30 ml) was added KOtBu (1.778 g, 15.84 mmol). The mixture was stirred at room temperature for 0.5 h, then the CAV06081 compound (2.10 g, 7.92 mmol) was added and stirring was continued for 1 h. The mixture was poured onto crushed ice and neutralized with a 2M KHSO ₄ solution. The precipitate was filtered off, washed with water and recrystallized from EtOAc / n-hexane to give CAB06082 (1.80 g, 69%) as a white crystalline solid. t _square = 140-143 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.59 (d, J = 2.4 Hz, 1H), 6.64 (dd, J = 8.6, 2.4 Hz, 1H), 7 72 (AA'BB ', 2H), 7.85 (d, J = 8.6 Hz, 1H), 7.89 (AA'BB', 2H), 8.87 (s, 2H), 10, 39 (s, 1H); MCHP (ER +): m / z 329.1 (100%, [M + H] ⁺ ); HRMS (ER +): calculated for C ₁₆ H ₁₀ F ₃ N ₅ [M + H] ⁺ : 330.0961, found: 330.0950

5 - ((4- (Benzyloxy) benzyl) (4H-1,2,4-triazol-4-yl) amino) -4 '- (trifluoromethyl) biphenyl-2-carbonitrile (САВ06097)

To a solution of the CAV06082 compound (0.660 g, 2.0 mmol) in DMF (10 ml) at room temperature was added NaH (0.90 g, 2.0 mmol, 60% in mineral oil). The mixture was stirred for 0.5 h, then benzyloxybenzyl chloride (0.465 g, 3.0 mmol) was added and stirring was continued for 18 h. The reaction mixture was diluted with EtOAc (50 ml), washed with water (3 × 30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO ₂ , EtOAc (undiluted)] to give CAB06097 (0.798 g, 76%) as a white solid. t _square = 173-175 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.06 (s, 4H), 6.73 (dd, J = 8.2 Hz, 2.7 Hz, 1H), 6.92 (d, J = 2.7 Hz, 1H), 6.96 (AA'BB ', 2H), 7.21 (AA'BB', 2H), 7.30-7.45 (m, 5H), 7.76 ( AA'BB ', 2H), 7.89 (d, J = 8.2 Hz, 1H), 7.92 (AA'BB', 2H), 8.75 (s, 2H); MCHP (ER +): m / z 526.2 (100%, [M + H] ⁺ ); HRMS (ER +): calculated for C ₃₀ H ₂₃ F ₃ N ₅ O [M + H] ⁺ : 526.1849, found: 526.1835; Analysis: Calculated for C ₃₀ H ₂₂ F ₃ N ₅ O: C, 68.56; H, 4.22; N, 18.33. Found: C, 68.3; H, 4.23; N, 18.3.

5 - ((4-Hydroxybenzyl) (4H-1,2,4-triazol-4-yl) amino) -4 '- (trifluoromethyl) biphenyl-2-carbonitrile (САВ06100).

To a solution of compound CAB06097 (0.585 g, 1.10 mmol) in THF (20 ml) and methanol (20 ml) was added Pd-C (0.10 g, 5% Pd). The mixture was stirred in an H2 atmosphere for 18 hours, then the catalyst was filtered off (through celite) and the volatiles were removed under reduced pressure. The residue was recrystallized from EtOAc to give CAB06100 (0.410 g, 85%) as colorless fine needles. t _square > 215 ° C (with decomposition); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.99 (s, 2H), 6.67 (AA'BB ', 2H), 6.73 (dd, J = 8.6, 2.3 Hz , 1H, 6.82 (d, J = 2.3 Hz, 1H), 7.06 (AA'BB ', 2H), 7.76 (d, J = 8.6 Hz, 1H), 7.91 (d, J = 8.2 Hz, 2H), 8.71 (s, 2H), 9.49 s, 1H); MCHP (ER +): m / z 436.0 (100%, [M + Hf); HRMS (ER +): calculated for C ₂₃ H ₁₇ F ₃ N ₅ O [M + H] ⁺ : 436.1380, found: 436.1371; Analysis: Calculated for C ₂₃ H ₁₆ F ₃ N ₅ O: C, 63.45; H, 3.70; N, 16.08. Found: C, 63.2; H, 3.66; N, 15.8.

4 - (((6-Cyano-4 '- (trifluoromethyl) biphenyl-3-yl) (4H-1,2,4-triazol-4-yl) amino) methyl) phenyl sulfamate (САВ06102)

To a solution of sulfamoyl chloride (0.399 g, 3.45 mmol) in DMA (1 ml) at 0 ° C was added a solution of compound САВ06100 (0.103 g, 0.237 mmol) in DMA (5 ml). The clear solution was stirred at 0 ° C for 2 hours and then at room temperature for 4 hours. EtOAc (50 ml) and water (20 ml) were added, the organic layer was separated, washed with water (2 × 30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give CAB06102 (0.107 g, 88%) as a white solid. t _square = 177-180 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.18 (s, 2H), 6.70 (dd, J = 8.6, 2.4 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 7.23 (AA'BB ', 2H), 7.41 (AA'BB, 2H), 7.64 (AA'BB', 2H) 7.88-7.94 ( m, 2H), 8.02 (s, 2H), 8.84 (s, 2H); MCHR (ER +): m / z 515.2 (60%, [M + H] ⁺ ), 446.2 (100%); HRMS (ER +): calculated for C ₂₃ H ₁₈ F ₃ N ₆ O ₃ S [M + H] ⁺ : 515.1108, found: 515.1098.

The following compounds were also prepared in accordance with the general synthesis schemes set forth above and in accordance with the preparation examples of the compounds of the present invention described above.

Compound 1 Compound 2

molecular weight (MM) 430.31, colorless crystals, melting point (t _pl. ) = 185-186 ° C MM 430.31, t _pl. = 195-197 ° C Compound 3 Compound 4

MM 446.49, t _pl. = 209-211 ° C MM 383.25

Compound 5 Compound 6

MM 462.33 MM 407.88, white solid Compound 7 Compound 8

MM 486.96 white solid MM 452.33, light orange solid Compound 9 Compound 10

MM 531.41, white solid MM 481.53, white solid Compound 11 Compound 12

MM 481.53 MM 381.44 white solid Compound 13 Compound 14

MM 460.52, white solid MM 360,42, white solid Compound 15 Compound 16

MM 439.5, almost white solid MM 374.45, almost white solid

Compound 17 Compound 18

MM 453.52, almost white solid MM 388.47, light yellow solid Compound 19 Compound 20

MM 467.55, almost white solid MM 376.42 white solid Compound 21 Compound 22

MM 455.5 MM 389.46 Compound 23 Compound 24

MM 468.54 MM 341,327 Compound 25 Compound 26

MM 420,4 MM 341.3 Compound 27 Compound 28

MM 420.45 MM 409.45

Compound 29 Compound 30

MM 488.63 MM 385.4 Compound 31 Compound 32

MM 468.48 MM 445.5 light yellow amorphous substance Compound 33 Compound 34

MM 403.39 MM 482.47 Compound 35 Compound 36

MM 433; 42 MM 512.5 Compound 37 Compound 38

MM 352.4 MM 390.44, white solid Compound 39 Compound 40

MM 469.52, white solid MM 374.45, white powder

Compound 41 Compound 42

MM 453.52, white powder MM 388.47, white powder Compound 43 Compound 44

MM 467.17, white powder MM 411.46, white solid Compound 45 Compound 46

MM 490.14 white solid MM 421.38 Compound 47 Compound 48

MM 500.46 Compound 49 Compound 50

Compound 51 Compound 52

Compound 53 Compound 54

Compound 55 Compound 56

Compound 57 Compound 58

Compound 59 Compound 60

Compound 61 Compound 62

Compound 63 Compound 64

Compound 65

Biological characteristics

Aromatase inhibition was investigated in accordance with Protocol 6. Inhibition of steroid sulfatase was investigated in accordance with Protocol 1.

Compound JEG3 cells, IC ₅₀ (nM) for aromatase JEG3 cells, IC ₅₀ (nM) for STS САВ06022 0.39 ± 0.09 DN САВ06021 <0.1 DN САВ06025 0.14 ± 0.01 17 ± 2 САВ06026 3.6 ± 0.4 DN САВ06043 1.6 ± 0.6 DN САВ06044 0.15 ± 0.03 2.3 ± 0.9 САВ06045 0.018 ± 0.01 0.13 ± 0.01 САВ06046 0.26 ± 0.12 DN САВ06049 0.015 ± 0.005 0.83 ± 0.15 САВ06052 0.33 ± 0.01 DN САВ06054 0.1 ± 0.02 2900 ± 180 САВ06059 0.05 ± 0.01 2900 ± 100 САВ06077 0.015 ± 0.001 22 ± 6 САВ06078 0.47 ± 0.18 55 ± 6 САВ06088 0.75 ± 0.18 240 ± 60 PMW04153 <0.1 0.12 ± 0.02 Compound 1 <0.1 DN Compound 2 960 ± 53 DN Compound 3 0.25 ± 0.03 3 ± 0.5 Compound 9 2.6 ± 0.2 3.9 ± 0.8 Compound 11 850 ± 104 1300 ± 265 Compound 12 <0.1 DN Compound 13 <0.1 41 ± 3 Compound 15 <0.1 60 ± 7 Compound 17 3.4 ± 0.2 43 ± 6 Compound 19 3.2 ± 0.1 181 ± 8 Compound 21 44 ± 5 DN Compound 22 13.77 ± 4.51 DN Compound 23 89.0 ± 10.15 2800 ± 984.9 Compound 24 0.14 ± 0.03 DN Compound 25 3.97 ± 0.72 485 ± 50.7 Compound 27 200 ± 5 5700 ± 1307 Compound 29 <0.1 1150 ± 50 Compound 30 0.35 ± 0.06 DN Compound 31 1.43 ± 0.55 0.15 ± 0.03 Compound 32 <0.1 9.7 ± 4.2 Compound 33 1.0 ± 0.3 DN Compound 34 0.8 ± 0.3 2.8 ± 0.9 Compound 35 <0.1 DN Compound 36 <0.1 0.1

Compound JEG3 cells, IC ₅₀ (nM) for aromatase JEG3 cells, IC ₅₀ (nM) for STS Compound 37 0.23 ± 0.04 DN Compound 40 8 ± 1.7 DN Compound 41 97 ± 2.7 4363 ± 554 Compound 44 3.1 ± 0.4 DN Compound 45 40.7 ± 4.5 292 ± 80 Compound 46 4.1 ± 0.2 DN Compound 47 5.60 ± 0.10 14.0 ± 0.87 Compound 50 4.03 ± 0.29 DN Compound 51 36 ± 1.7 198 ± 37 Compound 56 1.82 ± 0.03 DN Compound 57 12.5 ± 2.3 62 ± 13 Compound 66 0.77 ± 0.21 6350 ± 650 DN = no data

All publications, patents, and patent applications referred to in the above description are incorporated herein by reference. For specialists in the art it should be obvious that without deviating from the scope and essence of the present invention, various modifications and changes can be made to it. Although the present invention has been described using specific preferred embodiments, it should be understood that the present invention as claimed is not limited to such specific embodiments. In fact, various modifications of the described methods of carrying out the present invention, which are obvious to those skilled in chemistry, biology or related fields of technology, are intended to be included within the scope of the following claims.

Claims (25)

1. The compound of formula V or Va

wherein
D is selected from the group consisting of linear hydrocarbon groups containing a carbon chain containing from 1 to 2 carbon atoms;
R ₄ is —CN;
R ₂ and R ₅ are H;
each of R ₃ and R _{6 is} independently selected from the group consisting of —H, halogen, —NR ₁₂ R ₁₃ and - (CH ₂ ) _0-1 R ₁₄ ;
where R ₁₂ and R ₁₃ together with the atoms to which they are attached, can form a monocyclic ring containing from 5 to 8 ring elements;
where R ₁₄ denotes

where each of R ₁₇ -R _{21 is} independently selected from the group consisting of -H, halogen, -O- (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkyl, -CN, -OH, -OBn, - OSO ₂ NR ₁₅ R ₁₆ , —O— (C ₁ -C ₆ ) alkyl;
where R ₁₅ and R ₁₆ are selected from H;
where each of R ₇ —R _{11 is} independently selected from the group consisting of —H, halogen, —OH, —OBn, —OSO ₂ NR ₁₅ R ₁₆ ;
where R ₁₅ and R _{16 are} independently selected from the group consisting of H;
or any pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein D is - (CH ₂ ) _n -, where n is 1 or 2. 3. The compound of claim 2, wherein D is —CH ₂ -. 4. The compound according to claim 1, in which R ₂ , R ₅ and R ₆ denote N. 5. The compound of claim 1, wherein R ₃ is - (CH ₂ ) _0-1 R ₁₄ . 6. The compound of claim 1, wherein R ₃ is

where each of R ₁₇ -R _{21 is} independently selected from the group consisting of —H, halogen, (C ₁ -C ₆ ) haloalkyl, —CN, —OH, —OSO ₂ NR ₁₅ R ₁₆ and —O— (C ₁ -C ₆ ) alkyl. 7. The compound of claim 1, wherein R ₃ is

wherein each of R ₁₇ —R _{21 is} independently selected from the group consisting of —H, halogen, (C ₁ -C ₆ ) haloalkyl, —OSO ₂ NH ₂ and —O- (C ₁ -C ₆ ) alkyl. 8. The compound of claim 1, wherein R ₃ is

where each of R ₁₇ —R ₂₁ is —H. 9. The compound of claim 1, wherein each of R ₇ -R _{11 is} independently selected from the group consisting of —H, —OH, —OSO ₂ NR ₁₅ R _16, and halogen. 10. The compound of claim 1, wherein at least one of R ₇ -R ₁₁ is halogen. 11. The compound of claim 1, wherein at least one of R ₇ —R ₁₁ is —OSO ₂ NR ₁₅ R ₁₆ . 12. The compound of claim 1, wherein at least one of R ₇ -R ₁₁ is halogen and at least one of R ₇ -R ₁₁ is —OSO ₂ NR ₁₅ R ₁₆ . 13. The compound of claim 1, wherein R ₈ is halogen. 14. The compound of claim 1, wherein R ₉ is —OSO ₂ NR ₁₅ R ₁₆ . 15. The compound of claim 1, wherein R ₁₅ is H and R ₁₆ is H. 16. The compound according to claim 1, described by formula VIII

in which each of R ₁₇ —R _{21 is} independently selected from the group consisting of —H, —CN, —OH, —OSO ₂ NR ₁₅ R ₁₆ , —F, —Cl, —Br, —I, and —O— (C ₁ -C ₆ ) alkyl, and where each of these groups is defined in paragraph 1. 17. The compound according to claim 1, in which the group - (CH ₂ ) _0-1 R ₁₄ represents -R ₁₄ . 18. The compound according to any one of paragraphs. 1-17, intended for the preparation of a medicament for the treatment of a pathological condition or disease associated with STS and aromatase. 19. The compound according to any one of paragraphs. 1-17, intended for the preparation of a medicament for the treatment of a pathological condition or disease associated with undesirable concentrations of STS and with undesirable concentrations of aromatase. 20. The compound according to any one of paragraphs. 1-17, designed to inhibit the activity of STS and / or to inhibit the activity of aromatase. 21. The compound according to any one of paragraphs. 1-17, designed to inhibit aromatase activity. 22. The compound according to any one of paragraphs. 1-17, designed to inhibit the activity of STS. 23. The compound according to any one of paragraphs. 1-17, intended to inhibit the activity of STS and to inhibit the activity of aromatase. 24. The compound according to any one of paragraphs. 1-17, intended for the preparation of a medicament for the treatment of breast cancer. 25. A pharmaceutical composition having an inhibitory effect against STS and / or aromatase, containing an effective amount of a compound according to any one of claims. 1-17 optionally in admixture with a pharmaceutically acceptable carrier, diluent, excipient or excipient.

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